Novel Spiro-benzo[c]chromene derivatives useful as modulators of the estrogen receptors

ABSTRACT

The present invention is directed to novel spiro-benzo[C]chromene derivatives, pharmaceutical compositions containing them and their use in the treatment of disorders mediated by one or more estrogen receptors. The compounds of the invention are useful in the treatment of disorders associated with the depletion of estrogen such as hot flashes, vaginal dryness, osteopenia and osteoporosis; hormone sensitive cancers and hyperplasia of the breast, endometrium, cervix and prostate; endometriosis, uterine fibroids, osteoarthritis and as contraceptive agents, alone or in combination with a progestogen or progestogen antagonist.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application60/560,753, filed on Jul. 19, 2004, which is incorporated by referenceherein in its entirety.

FIELD OF THE INVENTION

The present invention is directed to novel spiro-benzo[c]chromenederivatives, pharmaceutical compositions containing them and their usein the treatment or prevention of disorders and diseases mediated by anestrogen receptor such as hot flashes, vaginal dryness, osteopenia,osteoporosis, hyperlipidemia, loss of cognitive function, degenerativebrain diseases, cardiovascular diseases, cerebrovascular diseases,hormone sensitive cancers and hyperplasia (in tissues including breast,endometrium, and cervix in women and prostate in men), endometriosis,uterine fibroids, osteoarthritis; and as contraceptive agents eitheralone or in combination with a progestogen or progestogen antagonist.The compounds of the invention are selective estrogen receptormodulators.

BACKGROUND OF THE INVENTION

Estrogens are a group of female hormones essential for the reproductiveprocess and for the development of the uterus, breasts, and otherphysical changes associated with puberty. Estrogens have an effect onvarious tissues throughout a woman's body, not only those involved inthe reproductive process, such as the uterus, breasts, and externalgenitalia, but also tissues in the central nervous system, bones, theliver, skin, and the urinary tract. The ovaries produce most of theestrogens in women's body.

Endogenous estrogens, such as 17β-estradiol and estrone, play a centralrole in the development of and maintenance of the female sex organs,mammary glands, and other sexual characteristics. In addition to theirrole as female sex hormone, estrogens are involved in the growth andfunction of a number of other tissues, such as the cardiovascularsystem, the central nervous system, and the skeleton, both in femalesand males. The significance of the estrogens in the development of thefemale reproductive system led to the development of a variety ofcompounds that interact with the estrogen receptors, such ascontraceptives and agents for treatment of breast cancers. Morerecently, intensive efforts have focused on the selective estrogenreceptor modulators for treatment and prevention of postmenopausalconditions, such as osteoporosis, coronary artery disease, depressionand Alzheimer disease.

Menopause is defined as the permanent cessation of menses due to loss ofovarian follicular function and the almost termination of estrogenproduction. The midlife transition of menopause is characterized by adecrease in estrogen that provokes both short-term and long-termsymptoms with the vasomotor, urogenital, cardiovascular, skeletal andcentral nervous systems, such as hot flushes, urogenital atrophy,increased risk of cardiovascular disease, osteoporosis, cognitive andpsychological impairment, including an increased risk of cognitivedisorders and Alzheimer's disease (AD).

Seventy-five percent of all women experience some occurrence ofvasomotor symptoms associated with the onset of menopause such as bodysweating and hot flushes. These complaints may begin several yearsbefore menopause and in some women may continue for more than 10 yearseither relatively constant, or as instant attacks without a definable,provoking cause.

Urogenital symptoms associated with the onset of menopause involving thevagina include a sensation of dryness, burning, itching, pain duringintercourse, superficial bleeding and discharge, along with atrophy andstenosis. Symptoms involving the urinary tract include a burningsensation during urination, frequent urgency, recurrent urinary tractinfections, and urinary incontinence. These symptoms have been reportedto occur in up to 50% of all women near the time of menopause and aremore frequent a few years after menopause. If left untreated, theproblems can become permanent.

Heart attack and stroke are major causes of morbility and mortalityamong senior women. Female morbility from these diseases increasesrapidly after menopause. Women who undergo premature menopause are atgreater coronary risk than menstruating women of similar age. Thepresence of serum estrogen has a positive effect on serum lipids. Thehormone promotes vasodilation of blood vessels, and enhances theformation of new blood vessels. Thus the decrease in serum estrogenlevels in postmenopausal women results in adverse cardiovascular effect.Additionally, it is theorized that differences in the ability of bloodto coagulate may account for the observed difference in the occurrenceof heart disease before and after menopause.

The skeleton is under a continuous process of bone degeneration andregeneration in a carefully regulated interaction among the bone cells.These cells are directly affected by estrogen. Estrogen deficiencyresults in a loss of bone structure and a decrease of bone strength.Rapid loss of bone mass during the year immediately following menopauseleads to postmenopausal osteoporosis and increased risk of fracture.

Estrogen deficiency is also one of the causes for the degenerativechanges in the central nervous system and may lead to Alzheimer'sdisease and decline of cognition. Recent evidence suggests anassociation between estrogen, menopause and cognition. Moreparticularly, it has been reported that estrogen replacement therapy andthe use of estrogen in women may prevent the development of AD andimprove cognitive function.

Hormone replacement therapy (HRT)—more specifically estrogen replacementtherapy (ERT)—is commonly prescribed to address the medical problemsassociated with menopause, and also to help hinder osteoporosis andprimary cardiovascular complications (such as coronary artery disease)in both a preventive and therapeutical manner. As such, HRT isconsidered a medical therapy for prolonging the average life span ofpostmenopausal women and providing a better quality of life.

ERT effectively relieves the climacteric symptoms and urogenitalsymptoms and has shown significant benefits in the prevention andtreatment of heart disease in postmenopausal women. Clinical reportshave shown that ERT lowered heart attack rates and mortality rates inpopulations that received ERT versus similar populations not on ERT. ERTinitiated soon after menopause may also help maintain bone mass forseveral years. Controlled investigations have shown that treatment withERT has a positive effect even in older women up to age of 75 years.

However, there are numerous undesirable effects associated with ERT thatreduce patient compliance. Venous thromboembolism, gallbladder disease,resumption of menses, mastodynia and a possible increased risk ofdeveloping uterine and/or breast cancer are the risks associated withERT. Up to 30% of women who were prescribed ERT did not fill theprescription, and the discontinuation rate is between 38% and 70%, withsafety concerns and adverse effects (bloating and break-throughbleeding) the most important reasons for discontinuation.

A new class of pharmacological agents known as Selective EstrogenReceptor Modulators or SERMs have been designed and developed asalternatives for HRT. Raloxifene, a nonsteroidal benzothiophere SERM ismarketed in the US and Europe for the prevention and treatment ofosteoporosis under the trademark of Evista®. Raloxifene has been shownto reduce bone loss and prevent fracture without adversely stimulatingendometrial and mammary tissue, though raloxifene is somewhat lessefficacious than ERT for protecting against bone loss. Raloxifene isunique and differs significantly from ERT in that it does not stimulatethe endometrium and has the potential for preventing breast cancer.Raloxifene has also demonstrated beneficial estrogen agonist effects oncardiovascular risk factors, more specifically through a rapid andsustained decrease in total and low-density lipoprotein cholesterollevels in patients treated with raloxifene. In addition, raloxifene hasbeen shown to reduce plasma concentration of homocysteine, anindependent risk factor for arteriosclerosis and thromboembolic disease.

However, raloxifene has been reported to exacerbate symptoms associatedwith menopause such as hot flushes and vaginal dryness, and does notimprove cognitive function in senior patients. Patients takingraloxifene have reported higher rates of hot flashes compared witheither placebo or ERT users and more leg cramps than placebo users,although women who took ERT had a higher incidence of vaginal bleedingand breast discomfort than raloxifene or placebo users.

As yet, neither raloxifene nor any of the other currently available SERMcompounds has been shown to have the ability to provide all the benefitsof currently available ERT such as controlling postmenopausal syndromeand preventing AD, without causing adverse side effects such asincreasing risk of endometrial and breast cancer and bleeding. Thusthere exists a need for compounds which are selective estrogen receptormodulators and which provide all of the benefits of ERT while alsoaddressing the vasomotor, urogenital and cognitive disorders orconditions associated with the decrease in systemic estrogen associatedwith menopause.

SUMMARY OF THE INVENTION

The present invention is directed to a compound of formula (I)

wherein

represents a single or double bond,

X, Y are selected from the group consisting of O, S, SO and SO₂;

Z is selected from the group consisting of O and S;

R¹ is selected from the group consisting of hydrogen, alkyl, cycloalkyl,aryl, aralkyl, heteroaryl and heteroaryl-alkyl; wherein the cycloalkyl,aryl, aralkyl, heteroaryl or heteroaryl-alkyl group is optionallysubstituted with one or more substituents independently selected fromhalogen, hydroxy, alkyl, alkoxy, —SH, —S(alkyl), SO₂, NO₂, CN, CO₂H,R^(C), —OR^(C), —SO₂—NR^(D)R^(E), —NR^(D)R^(E), NR^(D)—SO₂—R^(F),-(alkyl)₀₋₄-C(O)NR^(D)R^(E), (alkyl)₀₋₄-NR^(D)—C(O)—R^(F),-(alkyl)₀₋₄-(Q)₀₋₁-(alkyl)₀₋₄-NR^(D)R^(E),-(alkyl)₀₋₄-(Q)₀₋₁-(alkyl)₀₋₄-C(O)—OR^(F),-(alkyl)₀₋₄-(Q)₀₋₁-(alkyl)₀₋₄-C(O)—NR^(D)R^(E) or-(alkyl)₀₋₄-C(O)-(alkyl)₀₋₄-C(O)—OR^(F);

wherein R^(C) is selected from the group consisting of alkyl,cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl,heteroaryl-alkyl, heterocycloalkyl and heterocycloalkyl-alkyl; whereinthe cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl,heteroaryl-alkyl, heterocycloalkyl or heterocycloalkyl-alkyl group isoptionally substituted with one or more substituents independentlyselected from halogen, hydroxy, alkyl, alkoxy, —SH, —S(alkyl), SO₂, NO₂,CN, CO₂H, R^(c), —SO₂—NR^(D)R^(E), NR^(D)R^(E), NR^(D)—SO₂—R^(F),-(alkyl)₀₋₄-C(O)—NR^(D)R^(E), -(alkyl)₀₋₄-NR^(D)—C(O)—R^(F),-(alkyl)₀₋₄-(Q)₀₋₁-(alkyl)₀₋₄-NR^(D)R^(E),-(alkyl)₀₋₄-(Q)₀₋₁-(alkyl)₀₋₄-C(O)—OR^(F),-(alkyl)₀₋₄-(Q)₀₋₁-(alkyl)₀₋₄-C(O)—NR^(D)R^(E) or-(alkyl)₀₋₄-C(O)-(alkyl)₀₋₄-C(O)—OR^(F);

wherein Q is selected from the group consisting of O, S, NH, N(alkyl)and —CH═CH—;

wherein R^(D) and R^(E) are each independently selected from the groupconsisting of hydrogen and alkyl; alternatively R^(D) and R^(E) aretaken together with the nitrogen atom to which they are bound to form a4 to 8 membered ring selected from the group consisting of heteroaryl orheterocycloalkyl; wherein the heteroaryl or heterocycloalkyl group isoptionally substituted with one or more substituents independentlyselected from halogen, hydroxy, alkyl, alkoxy, carboxy, amino,alkylamino, dialkylamino, nitro or cyano;

wherein R^(F) is selected from the group consisting of hydrogen, alkyl,cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl,heteroaryl-alkyl, heterocycloalkyl and heterocycloalkyl-alkyl; whereinthe cycloalkyl, aryl, heteroaryl, heteroaryl-alkyl, heterocycloalkyl orheterocycloalkyl-alkyl group is optionally substituted with one or moresubstituents independently selected from halogen, hydroxy, alkyl,alkoxy, carboxy, amino, alkylamino, dialkylamino, nitro or cyano;

R² is selected from the group consisting of hydroxy, alkyl, cycloalkyl,aryl, aralkyl, heteroaryl and heteroaryl-alkyl; wherein the cycloalkyl,aryl, aralkyl, heteroaryl or heteroaryl-alkyl group is optionallysubstituted with one or more substituents independently selected fromhalogen, hydroxy, alkyl, alkoxy, —SH, —S(alkyl), SO₂, NO₂, CN, CO₂H,R^(C), —OR^(C), —SO₂—NR^(D)R^(E), —NR^(D)R^(E), NR^(D)—SO₂—R^(F),-(alkyl)₀₋₄-C(O)NR^(D)R^(E), (alkyl)₀₋₄-NR^(D)—C(O)—R^(F),-(alkyl)₀₋₄-(Q)₀₋₁-(alkyl)₀₋₄-NR^(D)R^(E),-(alkyl)₀₋₄-(Q)₀₋₁-(alkyl)₀₋₄-C(O)—OR^(F),-(alkyl)₀₋₄-(Q)₀₋₁-(alkyl)₀₋₄-C(O)—NR^(D)R^(E) or-(alkyl)₀₋₄-C(O)-(alkyl)₀₋₄-C(O)—OR^(F);

alternatively, R¹ and R² are taken together with the carbon atom towhich they are bound to form C(O);

m is an integer selected from 0 to 4;

R³ is independently selected from the group consisting of halogen,hydroxy, R^(C), amino, alkylamino, dialkylamino, nitro, cyano, SO₂,—C(O)R^(G), —C(O)OR^(G), —OC(O)R^(G), —OC(O)OR^(G), —OC(O)N(R^(G))₂,—N(R^(G))C(O)R^(G), —OSi(R^(G))₃—OR^(G), —SO₂N(R^(G))₂,—O-(alkyl)₁₋₄-C(O)R^(G) and —O-(alkyl)₁₋₄-C(O)OR^(G);

wherein each R^(G) is independently selected from hydrogen, alkyl, aryl,aralkyl and 1,7,7-trimethyl-2-oxabicyclo[2.2.1]heptan-3-one; wherein thealkyl, aryl or aralkyl group is optionally substituted with one or moresubstituents independently selected from alkyl, halogenated alkyl,alkoxy, halogen, hydroxy, nitro, cyano, —OC(O)-alkyl or —C(O)O-alkyl;alternatively two R^(G) groups are taken together with the nitrogen atomto which they are bound to form a heterocycloalkyl group; wherein theheterocycloalkyl group is optionally substituted with one or moresubstituents independently selected from halogen, hydroxy, alkyl,alkoxy, carboxy, amino, alkylamino, dialkylamino, nitro or cyano;

I is an integer selected from 0, 1;

In one aspect, the invention is a pharmaceutical composition comprisinga pharmaceutically acceptable carrier and any of the compounds describedabove. In a second aspect, the invention is a pharmaceutical compositionmade by mixing any of the compounds described above and apharmaceutically acceptable carrier. In another aspect, the invention isa process for making a pharmaceutical composition comprising mixing anyof the compounds described above and a pharmaceutically acceptablecarrier.

The invention also provides methods of treating a disorder mediated byone or more estrogen receptors in a subject in need thereof comprisingadministering to the subject a therapeutically effective amount of anyof the compounds or pharmaceutical compositions described above.

One embodiment of this aspect of the invention is a method ofcontraception comprising administering to a subject in need thereofco-therapy with a therapeutically effective amount of a compound offormula (I) with a progestogen or progestogen antagonist.

The invention also relates to the use of any of the compounds describedherein in the preparation of a medicament for treating: (a) hot flashes,(b) vaginal dryness, (c) osteopenia, (d) osteoporosis, (e)hyperlipidemia, (f) loss of cognitive function, (g) a degenerative braindisorder, (h) cardiovascular disease, (i) cerebrovascular disease (j)breast cancer, (k) endometrial cancer, (l) cervical cancer, (m) prostatecancer, (n) benign prostatic hyperplasia, (O) endometriosis, (p) uterinefibroids, (q) osteoarthritis and for (r) contraception in a subject inneed thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to a compound of formula (I)

wherein X, Y, Z, R¹, R², R³, m, and l are as herein defined, useful forthe treatment of disorders mediated by an estrogen receptor. Moreparticularly, the compounds of the present invention are useful for thetreatment and prevention of disorders mediated by the estrogen-α andestrogens-β receptors. More preferably, the compounds of the presentinvention are tissue selective estrogen receptor modulators.

The compounds of the present invention are useful in the treatment ofdisorders associated with the depletion of estrogen, hormone sensitivecancers and hyperplasia, endometriosis, uterine fibroids, osteoarthritisand as contraceptive agents, alone or in combination with a progestogenor progestogen antagonist.

More particularly, the compounds of the present invention are useful inthe treatment of a condition or disorder selected from the groupconsisting of hot flashes, vaginal dryness, osteopenia, osteoporosis,hyperlipidemia, loss of cognitive function, degenerative brain diseases,cardiovascular diseases, cerebrovascular diseases, cancer or hyperplasiaof the breast tissue, cancer or hyperplasia of the endometrium, canceror hyperplasia of the cervix, cancer or hyperplasia of the prostate,endometriosis, uterine fibroids and osteoarthritis; and as acontraceptive agent. Preferably, the disorder is selected from the groupconsisting of osteoporosis, hot flashes, vaginal dryness, breast cancer,and endometriosis.

In the compound of formula (I), the relative orientation of the groupsR¹ and R² is not intended to be fixed, rather both possible orientationsof the groups are intended to be included within the definition of thecompound of formula (I).

In an embodiment of the present invention are compounds of formula (I)wherein X is S, Y is S and Z is O. In another embodiment of the presentinvention are compounds of formula (I) wherein X is O, Y is O and Z isO.

In an embodiment of the present invention R¹ is selected from the groupconsisting of hydrogen and lower alkyl. Preferably, R¹ is hydrogen.

In an embodiment of the present invention R¹ is hydrogen and R² is inthe R stereo-configuration. In another embodiment of the presentinvention R¹ is hydrogen and R² is in the S stereo-configuration.

In an embodiment of the present invention R¹ is selected from the groupconsisting of hydrogen, lower alkyl, aryl, aralkyl, heteroaryl andheteroaryl-(lower alkyl); wherein the aryl, aralkyl, heteroaryl orheteroaryl-(lower alkyl) group is optionally substituted with one to twosubstituents independently selected from halogen, hydroxy, lower alkyl,lower alkoxy, —SH, —S(lower alkyl), SO₂, NO₂, CN, CO₂H, R^(C),—SO₂—NR^(D)R^(E), —NR^(D)R^(E), NR^(D)—SO₂—R^(F),-(alkyl)₀₋₄-C(O)NR^(D)R^(E), (alkyl)₀₋₄-NR^(D)—C(O)—R^(F),-(alkyl)₀₋₄-(Q)₀₋₁-(alkyl)₀₋₄-NR^(D)R^(E),-(alkyl)₀₋₄-(Q)₀₋₁-(alkyl)₀₋₄-C(O)—OR^(F),-(alkyl)₀₋₄-(Q)₀₋₁-(alkyl)₀₋₄-C(O)—NR^(D)R^(E) or-(alkyl)₀₋₄-C(O)-(alkyl)₀₋₄-C(O)—OR^(F).

Preferably R¹ is selected from the group consisting of hydrogen, loweralkyl, aryl, aralkyl, heteroaryl and heteroaryl-(lower alkyl); whereinthe aryl, aralkyl, heteroaryl or heteroaryl-(lower alkyl) group isoptionally substituted with one to two substituents independentlyselected from halogen, hydroxy, lower alkyl, lower alkoxy, —SH, —S(loweralkyl), SO₂, NO₂, CN, CO₂H, R^(C) or NR^(D)R^(E), More preferably R¹ isselected from the group consisting of hydrogen and lower alkyl. Morepreferably still R¹ is selected from the group consisting of hydrogenand methyl.

In an embodiment of the present invention R^(C) is selected from thegroup consisting of lower alkyl, aryl, aralkyl, heteroaryl,heteroaryl-(lower alkyl), heterocycloalkyl and heterocycloalkyl-(loweralkyl); wherein the aryl, aralkyl, heteroaryl, heteroaryl-(lower alkyl),heterocycloalkyl or heterocycloalkyl-(lower alkyl) group is optionallysubstituted with one to two substituents independently selected fromhalogen, hydroxy, lower alkyl, lower alkoxy, —SH, —S(alkyl), SO₂, NO₂,CN, CO₂H, R^(C), —SO₂—NR^(D)R^(E), NR^(D)—SO₂—R^(F),-(alkyl)₀₋₄-C(O)—NR^(D)R^(E), -(alkyl)₀₋₄-NR^(D)—C(O)—R^(F),-(alkyl)₀₋₄-(Q)₀₋₁-(alkyl)₀₋₄-NR^(D)R^(E),-(alkyl)₀₋₄-(Q)₀₋₁-(alkyl)₀₋₄-C(O)—OR^(F),-(alkyl)₀₋₄-(Q)₀₋₁-(alkyl)₀₋₄-C(O)—NR^(D)R^(E) or-(alkyl)₀₋₄-C(O)-(alkyl)₀₋₄-C(O)—OR^(F).

Preferably, R^(C) is selected from the group consisting of lower alkyl,aryl, aralkyl, heteroaryl, heteroaryl-(lower alkyl), heterocycloalkyland heterocycloalkyl-(lower alkyl); wherein the aryl, aralkyl,heteroaryl, heteroaryl-(lower alkyl), heterocycloalkyl orheterocycloalkyl-(lower alkyl) group is optionally substituted with oneto two substituents independently selected from halogen, hydroxy, loweralkyl, lower alkoxy, —SH, —S(alkyl), SO₂, NO₂, CN, CO₂H, R^(C) orNR^(D)R^(E).

In an embodiment of the present invention, Q is selected from the groupconsisting of O, S and —CH═CH—. Preferably, Q is selected from the groupconsisting of O and —CH═CH—, more preferably Q is O.

In an embodiment of the present invention R^(D) and R^(E) are eachindependently selected from the group consisting of hydrogen and loweralkyl. In another embodiment of the present invention, R^(D) and R^(E)are taken together with the nitrogen atom to which they are bound toform a 5 to 6 membered ring selected from the group consisting ofheteroaryl or heterocycloalkyl; wherein the heteroaryl orheterocycloalkyl group is optionally substituted with one to twosubstituents independently selected from halogen, hydroxy, lower alkyl,lower alkoxy, carboxy, amino, (lower alkyl)-amino, di(lower alkyl)amino,nitro or cyano.

In an embodiment of the present invention R^(F) is selected from thegroup consisting of hydrogen, lower alkyl, aryl, aralkyl, heteroaryl,heteroaryl-(lower alkyl), heterocycloalkyl and heterocycloalkyl-(loweralkyl); wherein the aryl, heteroaryl, heteroaryl-(lower alkyl),heterocycloalkyl or heterocycloalkyl-(lower alkyl) group is optionallysubstituted with one to two substituents independently selected fromhalogen, hydroxy, lower alkyl, lower alkoxy, carboxy, amino, (loweralkyl)-amino, di(lower alkyl)amino, nitro or cyano.

In an embodiment of the present invention R² is selected from the groupconsisting of hydroxy, lower alkyl, aryl, aralkyl, heteroaryl andheteroaryl-(lower alkyl); wherein the aryl, aralkyl, heteroaryl orheteroaryl-(lower alkyl) group is optionally substituted with one to twosubstituents independently selected from halogen, hydroxy, lower alkyl,lower alkoxy, —SH, —S(lower alkyl), SO₂, NO₂, CN, CO₂H, R^(C), —OR^(C),—SO₂—NR^(D)R^(E), —NR^(D)R^(E), -(alkyl)₀₋₄-C(O)NR^(D)R^(E),(alkyl)₀₋₄-NR^(D)—C(O)—R^(F), -(alkyl)₀₋₄-(Q)₀₋₁-(alkyl)₀₋₄-NR^(D)R^(E),-(alkyl)₀₋₄-(Q)₀₋₁-(alkyl)₀₋₄-C(O)—OR^(F),-(alkyl)₀₋₄-(Q)₀₋₁-(alkyl)₀₋₄-C(O)—NR^(D)R^(E) or-(alkyl)₀₋₄-C(O)-(alkyl)₀₋₄-C(O)—OR^(F). Preferably, R² is selected fromthe group consisting of hydroxy, lower alkyl, aryl, aralkyl, heteroaryland heteroaryl-(lower alkyl); wherein the aryl, aralkyl, heteroaryl orheteroaryl-(lower alkyl) group is optionally substituted with one to twosubstituents independently selected from halogen, hydroxy, lower alkyl,lower alkoxy, —SH, —S(lower alkyl), SO₂, NO₂, CN, CO₂H, R^(C), —OR^(C)or —NR^(D)R^(E). More preferably, R² is selected from the groupconsisting of hydroxy, aryl, 4-(1-heterocycloalkyl-alkoxy)-phenyl,4-(di(alkyl)amino-alkoxy)-phenyl, 4-(di(alkyl)amino)-phenyl and4-aralkyloxy-phenyl. More preferably still, R² is selected from thegroup consisting of hydroxy, phenyl, 4-(1-piperidinyl-ethoxy)-phenyl,4-(1-pyrrolidinyl-ethoxy)-phenyl, 4-(4-morpholinyl-ethoxy)-phenyl,4-(1-azepinyl-ethoxy)-phenyl, 4-(diethylamino-ethoxy)-phenyl,4-(dimethylamino-ethoxy)-phenyl, 4-(dimethylamino)-phenyl,4-benzyloxy-phenyl and 4-(1-piperidinyl-n-propoxy)-phenyl. Morepreferably still, R² is selected from the group consisting of phenyl,4-(1-piperidinyl-ethoxy)-phenyl, 4-(1-pyrrolidinyl-ethoxy)-phenyl,4-(4-morpholinyl-ethoxy)-phenyl, 4-(1-azepinyl-ethoxy)-phenyl,4-(diethylamino-ethoxy)-phenyl, 4-(dimethylamino-ethoxy)-phenyl,4-(dimethylamino)-phenyl and 4-(1-piperidinyl-n-propoxy)-phenyl. Morepreferably still, R² is selected from the group consisting of phenyl,4-(1-piperidinyl-ethoxy)-phenyl, 4-(1-pyrrolidinyl-ethoxy)-phenyl,4-(4-morpholinyl-ethoxy)-phenyl, 4-(1-azepinyl-ethoxy)-phenyl,4-(diethylamino-ethoxy)-phenyl, 4-(dimethylamino-ethoxy)-phenyl and4-(dimethylamino)-phenyl. More preferably still, R² is selected from thegroup consisting of phenyl, 4-(1-piperidinyl-ethoxy)-phenyl,4-(1-pyrrolidinyl-ethoxy)-phenyl, 4-(4-morpholinyl-ethoxy)-phenyl,4-(1-azepinyl-ethoxy)-phenyl, 4-(dimethylamino-ethoxy)-phenyl and4-(dimethylamino)-phenyl.

In another embodiment of the present invention R² is selected from thegroup consisting of -(alkyl)₀₋₄-(Q)₀₋₁-(alkyl)₀₋₄-NR^(D)R^(E) and-(alkyl)₀₋₄-(Q)₀₋₁-(alkyl)₀₋₄-C(O)OR^(F). In yet another embodiment ofthe present invention, R² is selected from the group consisting of-(alkyl)₀₋₄-(Q)₀₋₁-(alkyl)₀₋₄-NR^(D)R^(E); wherein R^(D) and R^(E) aretaken together with the nitrogen atom to which they are bound to form a5 to 7 membered ring selected from the group consisting of heteroaryland heterocycloalkyl.

In an embodiment of the present invention are compound of formula (I)wherein R¹ and R² are taken together with the carbon atom to which theyare bound to form C(O).

In an embodiment of the present invention R³ is selected from the groupconsisting of halogen, hydroxy, R^(C), amino, (lower alkyl)-amino,di(lower alkyl)amino, nitro, cyano, —OC(O)R^(G), —OC(O)OR^(G),—OC(O)N(R^(G))₂, —OSi(R^(G))₃—OR^(G), —O-(alkyl)₁₋₄-C(O)R^(G) and—O-(alkyl)₁₋₄-C(O)OR^(G).

Preferably, R³ is selected from the group consisting of hydroxy, R^(C),—OC(O)R^(G), —OC(O)OR^(G), —OC(O)N(R^(G))₂, —OSi(R^(G))₃—OR^(G),—O-(alkyl)₁₋₄-C(O)R^(G) and —O-(alkyl)₁₋₄-C(O)OR^(G).

More preferably, R³ is selected from the group consisting of halogen,hydroxy, lower alkoxy, (lower alkyl-di(lower alkyl))-silyloxy,—OC(O)-(lower alkyl), —OC(O)—C(phenyl)-OC(O)-(lower alkyl),—OC(O)-(1,7,7-trimethyl-2-oxabicyclo[2.2.1]heptan-3-one) and—OC(O)—C(CH₃)(CF₃)-phenyl. More preferably still R³ is selected from thegroup consisting of fluoro, hydroxy, methoxy, t-butyl-dimethyl-silyloxy,—OC(O)-t-butyl, —OC(O)—C(phenyl)-OC(O)CH₃,—OC(O)-(1,7,7-trimethyl-2-oxabicyclo[.2.1]heptan-3-one) and—OC(O)—C(CH₃)(CF₃)-phenyl. More preferably still, R³ is selected fromthe group consisting of hydroxy and —OC(O)-t-butyl.

In an embodiment of the present invention R^(G) is selected fromhydrogen, lower alkyl, aryl, aralkyl and1,7,7-trimethyl-2-oxabicyclo[2.2.1]heptan-3-one; wherein the alkyl, arylor aralkyl group is optionally substituted with one to two substituentsindependently selected from lower alkyl, halogenated lower alkyl, loweralkoxy, halogen, hydroxy, nitro, cyano, —OC(O)-(lower alkyl) and—C(O)O-(lower alkyl).

In another embodiment of the present invention two R^(G) groups aretaken together with the nitrogen atom to which they are bound to form a5 to 6 membered heterocycloalkyl group; wherein the heterocycloalkylgroup is optionally substituted with one to two substituentsindependently selected from halogen, hydroxy, lower alkyl, lower alkoxy,carboxy, amino, (lower alkyl)-amino, di(lower alkyl)amino, nitro orcyano.

In an embodiment of the present invention, m is an integer selected from0 to 2. Preferably, m is an integer selected from 0 to 1. Morepreferably m is 1.

In an embodiment of the present invention, m is an integer selected from1 to 2. Preferably, m is 1.

For use in medicine, the salts of the compounds of this invention referto non-toxic “pharmaceutically acceptable salts.” Other salts may,however, be useful in the preparation of compounds according to thisinvention or of their pharmaceutically acceptable salts. Suitablepharmaceutically acceptable salts of the compounds include acid additionsalts which may, for example, be formed by mixing a solution of thecompound with a solution of a pharmaceutically acceptable acid such ashydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinicacid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonicacid or phosphoric acid. Furthermore, where the compounds of theinvention carry an acidic moiety, suitable pharmaceutically acceptablesalts thereof may include alkali metal salts, e.g., sodium or potassiumsalts; alkaline earth metal salts, e.g., calcium or magnesium salts; andsalts formed with suitable organic ligands, e.g., quaternary ammoniumsalts. Thus, representative pharmaceutically acceptable salts includethe following:

acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate,borate, bromide, calcium edetate, camsylate, carbonate, chloride,clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate,esylate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate,pantothenate, phosphate/diphosphate, polygalacturonate, salicylate,stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate,tosylate, triethiodide and valerate.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds which are readily convertible invivo into the required compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with the compoundspecifically disclosed or with a compound which may not be specificallydisclosed, but which converts to the specified compound in vivo afteradministration to the patient. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

Where the compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where the compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. It is to be understood that all such isomers and mixturesthereof are encompassed within the scope of the present invention.Furthermore, some of the crystalline forms for the compounds may existas polymorphs and as such are intended to be included in the presentinvention. In addition, some of the compounds may form solvates withwater (i.e., hydrates) or common organic solvents, and such solvates arealso intended to be encompassed within the scope of this invention.

As used herein, the term “degenerative brain disease” shall includecognitive disorder, dementia, regardless of underlying cause andAlzheimer's disease.

As used herein, the term “cardiovascular disease” shall include elevatedblood lipid levels, coronary arthrosclerosis and coronary heart disease.

As used herein, the term “cerebrovascular disease” shall includeabnormal regional cerebral blood flow and ischemic brain damage.

As used herein, the term “progestogen antagonist” shall includemifepristone, J-867 (Jenapharm/TAP Pharmaceuticals), J-956(Jenapharm/TAP Pharmaceuticals), ORG-31710 (Organon), ORG-32638(Organon), ORG-31806 (Organon), onapristone and PRA248 (Wyeth).

As used herein, unless otherwise noted, “halogen” shall mean chlorine,bromine, fluorine and iodine.

As used herein, unless otherwise noted, the term “alkyl” whether usedalone or as part of a substituent group, include straight and branchedchain compositions of one to eight carbon atoms. For example, alkylradicals include methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, t-butyl, pentyl and the like. Unless otherwise noted, “lower”when used with alkyl means a carbon chain composition of 1-4 carbonatoms. Similarly, the group “-(alkyl)₀₋₄-”, whether alone or as part ofa large substituent group, shall me the absence of an alkyl group or thepresence of an alkyl group comprising one to four carbon atoms. Suitableexamples include, but are not limited to —CH₂—, —CH₂CH₂—, CH₂—CH(CH₃)—,CH₂CH₂CH₂—, —CH₂CH(CH₃)CH₂—, CH₂CH₂CH₂CH₂—, and the like.

As used herein, unless otherwise noted, “alkoxy” shall denote an oxygenether radical of the above described straight or branched chain alkylgroups. For example, methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy,n-hexyloxy and the like.

As used herein, unless otherwise noted, “aryl” shall refer tounsubstituted carbocyclic aromatic groups such as phenyl, naphthyl, andthe like.

As used herein, unless otherwise noted, “aralkyl” shall mean any loweralkyl group substituted with an aryl group such as phenyl, naphthyl andthe like. Suitable examples include benzyl, phenylethyl, phenylpropyl,naphthylmethyl, and the like.

As used herein, unless otherwise noted, the term “cycloalkyl” shall meanany stable 3-8 membered monocyclic, saturated ring system, for examplecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl andcyclooctyl.

As used herein, unless otherwise noted, the term “cycloalkyl-alkyl”shall mean any lower alkyl group substituted with a cycloalkyl group.Suitable examples include, but are not limited to cyclohexyl-methyl,cyclopentyl-methyl, cyclohexyl-ethyl, and the like.

As used herein, unless otherwise noted, the terms “acyloxy” shall mean aradical group of the formula —O—C(O)—R where R is alkyl, aryl oraralkyl, wherein the alkyl, aryl or aralkyl is optionally substituted.As used herein, the term “carboxylate” shall mean a radical group of theformula —C(O)O—R where R is alkyl, aryl or aralkyl, wherein the alkyl,aryl or aralkyl is optionally substituted.

As used herein, unless otherwise noted, “heteroaryl” shall denote anyfive or six membered monocyclic aromatic ring structure containing atleast one heteroatom selected from the group consisting of O, N and S,optionally containing one to three additional heteroatoms independentlyselected from the group consisting of O, N and S; or a nine or tenmembered bicyclic aromatic ring structure containing at least oneheteroatom selected from the group consisting of O, N and S, optionallycontaining one to four additional heteroatoms independently selectedfrom the group consisting of O, N and S. The heteroaryl group may beattached at any heteroatom or carbon atom of the ring such that theresult is a stable structure.

Examples of suitable heteroaryl groups include, but are not limited to,pyrrolyl, furyl, thienyl, oxazolyl, imidazolyl, purazolyl, isoxazolyl,isothiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, pyranyl, furazanyl, indolizinyl, indolyl,isoindolinyl, indazolyl, benzofuryl, benzothienyl, benzimidazolyl,benzthiazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl,isothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,naphthyridinyl, pteridinyl, and the like.

As used herein, unless otherwise noted, the term “heteroaryl-alkyl”shall mean any lower alkyl group substituted with a heteroaryl group.Suitable examples include, but are not limited to pyridyl-methyl,isoquinolinyl-methyl, thiazolyl-ethyl, furyl-ethyl, and the like.

As used herein, the term “heterocycloalkyl” shall denote any five toseven membered monocyclic, saturated or partially unsaturated ringstructure containing at least one heteroatom selected from the groupconsisting of O, N and S, optionally containing one to three additionalheteroatoms independently selected from the group consisting of O, N andS; or a nine to ten membered saturated, partially unsaturated orpartially aromatic bicyclic ring system containing at least oneheteroatom selected from the group consisting of O, N and S, optionallycontaining one to four additional heteroatoms independently selectedfrom the group consisting of O, N and S. The heterocycloalkyl group maybe attached at any heteroatom or carbon atom of the ring such that theresult is a stable structure.

Examples of suitable heteroaryl groups include, but are not limited to,pyrrolinyl, pyrrolidinyl, dioxalanyl, imidazolinyl, imidazolidinyl,pyrazolinyl, pyrazolidinyl, piperidinyl, dioxanyl, morpholinyl,dithianyl, thiomorpholinyl, piperazinyl, trithianyl, indolinyl,chromenyl, 3,4-methylenedioxyphenyl, 2,3-dihydrobenzofuryl, and thelike.

As used herein, unless otherwise noted, the term“heterocycloalkyl-alkyl” shall mean any lower alkyl group substitutedwith a heterocycloalkyl group. Suitable examples include, but are notlimited to piperidinyl-methyl, piperazinyl-methyl, piperazinyl-ethyl,morpholinyl-methyl, and the like.

As used herein, the notation “*” shall denote the presence of astereogenic center.

When a particular group is “substituted” (e.g., cycloalkyl, aryl,heteroaryl, heterocycloalkyl), that group may have one or moresubstituents, preferably from one to five substituents, more preferablyfrom one to three substituents, most preferably from one to twosubstituents, independently selected from the list of substituents.Additionally when aralkyl, heteroaryl-alkyl, heterocycloalkyl-alkyl orcycloalkyl-alkyl group is substituted, the substituent(s) may be on anyportion of the group (i.e. the substituent(s) may be on the aryl,heteroaryl, heterocycloalkyl, cycloalkyl or the alkyl portion of thegroup.)

With reference to substituents, the term “independently” means that whenmore than one of such substituents is possible, such substituents may bethe same or different from each other.

Under standard nomenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.Thus, for example, a “phenylC₁-C₆alkylaminocarbonylC₁-C₆alkyl”substituent refers to a group of the formula

Unless otherwise noted, when naming substituents such as R³ group, thefollowing numbering of the core structure will be applied. The capitalletters A, B, C and D will be used to designate specific rings of thetetracyclic core structure.

Abbreviations used in the specification, particularly the Schemes andExamples, are as follows

Ac=Acetyl group (—C(O)—CH₃)AD=Alzheimer's diseaseCSA=Camphor sulfonic acid

DCC=1,3-Dicyclohexylcarbodiimide DCM=DichloromethaneDEAD=Diethylazodicarboxylate DIAD=Diisopropylazodicarboxylate

Dibal-H=Diisobutyl aluminum hydride

DIC Diisopropylcarbodiimide DIPEA or DIEA=DiisopropylethylamineDMA=Dimethylacetamide DMAP=N,N-Dimethylaminopyridine

DMF=Dimethyl formamide

DMSO=Dimethylsulfoxide

ERT=Estrogen replacement therapyEt=ethyl (i.e. —CH₂CH₃)EtOAc=Ethyl acetateFBS=Fetal bovine serumHPLC=High pressure liquid chromatographyHRT=Hormone replacement therapyIPA=Isopropyl alcoholiPr₂NH=Diisopropylamine

MeOH=Methanol Ph=Phenyl PIV or Piv=Pivaloyl P(Ph)₃=Triphenylphosphine

PPTS=Pyridinium p-toluenesulfonateRochelle Solution=Aqueous solution of potassium sodium tartratetetrahydrateSERM=Selective estrogen receptor modulatorTBAF=Tetra(n-butyl)ammonium fluoride

TBDMS=Tert-butyldimethylsilane TBS=Tert-butyl-dimethyl-silyl

TBSCl=Tert-butyl-dimethyl-silyl chloride

TEA or Et₃N=Triethylamine

TFA=Trifluoroacetic acid

THF=Tetrahydrofuran

TsOH=Tosic acid

The term “subject” as used herein, refers to an animal, preferably amammal, most preferably a human, who has been the object of treatment,observation or experiment.

The term “therapeutically effective amount” as used herein, means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes alleviation of the symptoms of thedisease or disorder being treated. Wherein the present inventiondirected to co-therapy comprising administration of one or morecompound(s) of formula I and a progestogen or progestogen antagonist,“therapeutically effective amount” shall mean that amount of thecombination of agents taken together so that the combined effect elicitsthe desired biological or medicinal response. For example, thetherapeutically effective amount of co-therapy comprising administrationof a compound of formula I and progestogen would be the amount of thecompound of formula I and the amount of the progestogen that when takentogether or sequentially have a combined effect that is therapeuticallyeffective. Further, it will be recognized by one skilled in the art thatin the case of co-therapy with a therapeutically effective amount, as inthe example above, the amount of the compound of formula I and/or theamount of the progestogen or progestogen antagonist individually may ormay not be therapeutically effective.

As used herein, the term “co-therapy” shall mean treatment of a subjectin need thereof by administering one or more compounds of formula I witha progestogen or progestogen antagonist, wherein the compound(s) offormula I and progestogen or progestogen antagonist are administered byany suitable means, simultaneously, sequentially, separately or in asingle pharmaceutical formulation. Where the compound(s) of formula Iand the progestogen or progestogen antagonist are administered inseparate dosage forms, the number of dosages administered per day foreach compound may be the same or different. The compound(s) of formula Iand the progestogen or progestogen antagonist may be administered viathe same or different routes of administration. Examples of suitablemethods of administration include, but are not limited to, oral,intravenous (iv), intramuscular (im), subcutaneous (sc), transdermal,and rectal. Compounds may also be administered directly to the nervoussystem including, but not limited to, intracerebral, intraventricular,intracerebroventricular, intrathecal, intracisternal, intraspinal and/orperi-spinal routes of administration by delivery via intracranial orintravertebral needles and/or catheters with or without pump devices.The compound(s) of formula I and the progestogen or progestogenantagonist may be administered according to simultaneous or alternatingregimens, at the same or different times during the course of thetherapy, concurrently in divided or single forms.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombinations of the specified ingredients in the specified amounts.

Compounds of formula (I) wherein X is S, Y is S and Z is O may beprepared

according to the processes outlined in Scheme 1.

More particularly, a suitably substituted compound of formula (II),where Z is O or S, a known compound or compound prepared by knownmethods, is reacted with a compound of formula (III), a known compound,in the presence of an organic base such as NaH, NaOMe, t-BuOK, and thelike, in an organic solvent such as THF, dioxlane, ethyl ether, and thelike, at a temperature in the range of about 0 to about 25° C., to yieldthe corresponding compound of formula (IV).

The compound of formula (IV) is reacted with a suitably substitutedcompound of formula (V), a known compound, in the presence of aninorganic acid such as sulfuric acid, hydrochloric acid, and the like oran organic acid such as pTSA, CSA, and like, in an organic solvent suchas benzene, toluene, THF, and the like, at a temperature in the range of0 to about 25° C., to yield the corresponding compound of formula (VI).

One skilled in the art will recognize that it may be necessary and/ordesirable to protect one or more of the R³ and/or R⁴ groups at any ofthe steps within the process described above. This may be accomplishedusing known protecting groups and know protection and de-protectionreagents and conditions, for example such as those described inProtective Groups in Organic Chemistry, ed. J. F. W. McOmie, PlenumPress, 1973; and T. W. Greene & P. G. M. Wuts, Protective Groups inOrganic Synthesis, John Wiley & Sons, 1991.

Accordingly, the compound of formula (VI) is reacted withdiisobutyl-aluminum hydride, L-selectride, and the like, in an organicsolvent such as toluene, benzene, THF, methylene chloride, and the like,at a reduced temperature in the range of about 0 to about −80° C., toyield the corresponding compound of formula (VII).

The compound of formula (VII) is reacted with a suitably substitutedcompound of formula (VIII), wherein MQ is lithium or a magnesium halidesuch as MgCl, MgBr or MgI, prepared from the corresponding known alkylor aryl halide by known methods, in an organic solvent such as THF,diethyl ether, dioxane, hexane, and the like, to yield the correspondingcompound of formula (IX).

The compound of formula (IX) is treated with a protic acid such as HCl,H₂SO₄, p-toluene sulfonic acid, camphor sulfonic acid (CSA), TFA, andthe like or a Lewis acid such as BF₃ etherate, AlCl₃, SnCl₄, and thelike, in a solvent such as toluene, methylene chloride, acetonitrile andthe like, to yield the corresponding compound of formula (X).

Alternatively, the compound of formula (IX) is treated with a reagentsuch as triphenylphosphine, tributylphosphine, and the like, or anazodicarboxamide such as DEAD, DIAD, and the like, in a solvent such astoluene, THF, and the like, to yield the corresponding compound offormula (X).

Compounds of formula (X) wherein R² is -(aryl)-O-(alkyl)₀₋₄-NR^(D)R^(E)may be prepared by reacting a suitably substituted compound of formula(X), wherein the R² group is -(aryl)-O-(alkyl)₀₋₄-Hal (Hal is selectedfrom Cl, Br or I) with a catalytic amount of iodine salt such as NaI,KI, NH₄NI, and the like and amine source NHR^(D)R^(E) such as dimethylamine, diethyl amine, pyrrolidine, piperidine, morphiline and the like,in a solvent such as DMF, DMSO, DMA and the like, to yield thecorresponding compound of formula (X). For example, a compound offormula (X*) wherein R², is -(aryl)-O-(alkyl)₀₋₄-NR^(D)R^(E) may beprepared according to the process outlined in Scheme 2.

One skilled in the art will recognize that it may be necessary and/ordesirable to protect one or more of the R³ groups at any of the stepswithin the process described above. This may be accomplished using knownprotecting groups and know protection and de-protection reagents andconditions, for example such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1991.

Compounds of formula (I) wherein one or more R³ are acyloxy may beprepared by reacting a suitably substituted compound of formula (I),wherein the R³ group(s) are hydroxy with a suitably substituted acidchloride, a suitably substituted carboxylic acid or a suitablysubstituted anhydride. For example, a compound of formula (I) whereinR³, at the 2 position, is acyloxy may be prepared according to theprocess outlined in Scheme 3.

Accordingly, a suitably substituted compound of formula (X) prepared asin Scheme 1, is reacted with a suitably substituted acid chloride, acompound of formula (XI), or a suitably substituted anhydride, acompound of formula (XII), wherein R^(G) is as defined above, a knowncompound or compound prepared by known methods, in the presence of anorganic amine such as TEA, DIPEA, pyridine, and the like, in ahalogenated organic solvent such as DCM, methylene chloride, chloroform,and the like, or in a hydrocarbon solvent such as benzene, toluene, andthe like, to yield the corresponding compound of formula (XIV).

Alternatively, the compound of formula (X) is reacted with a suitablysubstituted carboxylic acid, a compound of formula (VIII), wherein R^(G)is as defined above, a known compound or compound prepared by knownmethods, in the presence of a coupling reagent such as DCC, DIC, and thelike, in an organic solvent such as DMF, THF, methylene chloride, andthe like, to yield the corresponding compound of formula (XIV).

Wherein the compound of formula (X), one or more of the R³ groups arehydroxy groups protected with a silyl protecting group such as TBS, thecompound of formula (X) is reacted with a tetra-alkyl ammonium fluoridesuch as TBAF, and the like, and then reacted with a suitably substitutedacid chloride of formula (XI), in an organic solvent such as THF,diethyl ether, and the like, to yield the corresponding compound offormula (X).

Where the processes for the preparation of the compounds according tothe invention give rise to mixture of stereoisomers, these isomers maybe separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their component enantiomers by standard techniques, such as theformation of diastereomeric pairs by salt formation with an opticallyactive acid, such as (−)-di-p-toluoyl-d-tartaric acid and/or(+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallizationand regeneration of the free base. The compounds may also be resolved byformation of diastereomeric esters or amides, followed bychromatographic separation and removal of the chiral auxiliary.Alternatively, the compounds may be resolved using a chiral HPLC column.

The compound of formula (VI) may be selectively hydrogenated to yieldthe corresponding compound of formula (XV), as shown in Scheme 4.

Accordingly, the compound of formula (VI) is reacted with hydrogen gas,at a pressure in the range of about 20 to about 100 psi, in the presenceof a metal catalyst such as Pd on C, Pt on C, Raney nickel, Pd(OH)₂, andthe like, to yield the corresponding compound of formula (XV), aspredominately the cis isomer.

Alternatively, the compound of formula (VI) is reacted with a hydridesuch as LAH, Cu hydride, SmI₂, Stryker's Reagent ([(Ph₃P)CuH]₆), and thelike, in an solvent such as THF, diethyl ether, and the like, at atemperature in the range of about −20 to about 60° C., to yield thecorresponding compound of formula (XV), as predominately the transisomer.

Alternatively still, the compound of formula (VI) is reacted withtriethyl silane, in the presence of an acid such as TFA, BF₃ etherate,Tin tertachloride, and the like, in an organic solvent such as methylenechloride, toluene, and the like, to yield the corresponding compound offormula (XV), as a mixture of cis and trans isomers.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1991. The protectinggroups may be removed at a convenient subsequent stage using methodsknown from the art.

The utility of the compounds of the instant invention to treat disordersmediated by an estrogen receptor may be determined according to theprocedures described in Examples 1-26, and herein.

The present invention therefore provides a method of treating disordersmediated by an estrogen receptor in a subject in need thereof whichcomprises administering any of the compounds as defined herein in aquantity effective to treat said disorder. The compound may beadministered to a patient by any conventional route of administration,including, but not limited to, intravenous, oral, subcutaneous,intramuscular, intradermal and parenteral. The quantity of the compoundwhich is effective for treating a disorder mediated by an estrogenreceptor is between 0.01 mg per kg and 20 mg per kg of subject bodyweight.

The present invention also provides pharmaceutical compositionscomprising one or more compounds of this invention in association with apharmaceutically acceptable carrier. Preferably these compositions arein unit dosage forms such as tablets, pills, capsules, powders,granules, sterile parenteral solutions or suspensions, metered aerosolor liquid sprays, drops, ampoules, autoinjector devices orsuppositories; for oral parenteral, intranasal, sublingual or rectaladministration, or for administration by inhalation or insufflation.Alternatively, the composition may be presented in a form suitable foronce-weekly or once-monthly administration; for example, an insolublesalt of the active compound, such as the decanoate salt, may be adaptedto provide a depot preparation for intramuscular injection. Forpreparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical carrier, e.g. conventionaltableting ingredients such as corn starch, lactose, sucrose, sorbitol,talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, andother pharmaceutical diluents, e.g. water, to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention, or a pharmaceutically acceptable saltthereof. When referring to these preformulation compositions ashomogeneous, it is meant that the active ingredient is dispersed evenlythroughout the composition so that the composition may be readilysubdivided into equally effective dosage forms such as tablets, pillsand capsules. This solid preformulation composition is then subdividedinto unit dosage forms of the type described above containing from 5 toabout 1000 mg of the active ingredient of the present invention. Thetablets or pills of the novel composition can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permits theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of material can be used for such enteric layers orcoatings, such materials including a number of polymeric acids with suchmaterials as shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude, aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions, include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin.

The method of treating a disorder mediated by an estrogen receptordescribed in the present invention may also be carried out using apharmaceutical composition comprising any of the compounds as definedherein and a pharmaceutically acceptable carrier. The pharmaceuticalcomposition may contain between about 5 mg and 1000 mg, preferably about10 to 500 mg, of the compound, and may be constituted into any formsuitable for the mode of administration selected. Carriers includenecessary and inert pharmaceutical excipients, including, but notlimited to, binders, suspending agents, lubricants, flavorants,sweeteners, preservatives, dyes, and coatings. Compositions suitable fororal administration include solid forms, such as pills, tablets,caplets, capsules (each including immediate release, timed release andsustained release formulations), granules, and powders, and liquidforms, such as solutions, syrups, elixers, emulsions, and suspensions.Forms useful for parenteral administration include sterile solutions,emulsions and suspensions.

Advantageously, compounds of the present invention may be administeredin a single daily dose, or the total daily dosage may be administered individed doses of two, three or four times daily. Furthermore, compoundsfor the present invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal skinpatches well known to those of ordinary skill in that art. To beadministered in the form of a transdermal delivery system, the dosageadministration will, of course, be continuous rather than intermittentthroughout the dosage regimen.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Moreover, when desired or necessary,suitable binders, lubricants, disintegrating agents and coloring agentscan also be incorporated into the mixture. Suitable binders include,without limitation, starch, gelatin, natural sugars such as glucose orbeta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium oleate, sodium stearate, magnesiumstearate, sodium benzoate, sodium acetate, sodium chloride and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum and the like.

The liquid forms may include suitably flavored suspending or dispersingagents such as the synthetic and natural gums, for example, tragacanth,acacia, methyl-cellulose and the like. For parenteral administration,sterile suspensions and solutions are desired. Isotonic preparationswhich generally contain suitable preservatives are employed whenintravenous administration is desired.

The compound of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine or phophatidylcholines.

Compounds of the present invention may also be delivered by the use ofmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds of the present invention may alsobe coupled with soluble polymers as targetable drug carriers. Suchpolymers can include polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamidephenol,polyhydroxyethylaspartamidephenol, or polyethyl-eneoxidepolylysinesubstituted with palmitoyl residue. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels.

Compounds of this invention may be administered in any of the foregoingcompositions and according to dosage regimens established in the artwhenever treatment of a disorder mediated by an estrogen receptor isrequired.

The daily dosage of the products may be varied over a wide range from 5to 1,000 mg per adult human per day. For oral administration, thecompositions are preferably provided in the form of tablets containing,1.0, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250 and 500 milligrams of theactive ingredient for the symptomatic adjustment of the dosage to thepatient to be treated. An effective amount of the drug is ordinarilysupplied at a dosage level of from about 0.01 mg/kg to about 20 mg/kg ofbody weight per day. Preferably, the range is from about 0.1 mg/kg toabout 10 mg/kg of body weight per day, and especially from about 0.5mg/kg to about 10 mg/kg of body weight per day. The compounds may beadministered on a regimen of 1 to 4 times per day.

Optimal dosages to be administered may be readily determined by thoseskilled in the art, and will vary with the particular compound used, themode of administration, the strength of the preparation, the mode ofadministration, and the advancement of the disease condition. Inaddition, factors associated with the particular patient being treated,including patient age, weight, diet and time of administration, willresult in the need to adjust dosages.

The following Examples are set forth to aid in the understanding of theinvention, and are not intended and should not be construed to limit inany way the invention set forth in the claims which follow thereafter.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds which are readily convertible invivo into the required compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with the compoundspecifically disclosed or with a compound which may not be specificallydisclosed, but which converts to the specified compound in vivo afteradministration to the patient. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

Following the procedures described in the Schemes and Examples above,representative compounds of the present invention were prepared, aslisted in Tables 1. For the stereo-configuration of the R² group, theR*-(−) and S*-(+) notations indicate that the exact orientation was notdetermined.

EXAMPLE 1 8-Hydroxy-1,4-dithia-spiro[4.5]dec-7-ene-7-carboxylic acidmethyl ester

To 1,4-dithia-spiro[4.5]decan-8-one (2.35 g, 12.5 mmol, 1.0 eq), in THF(10 mL) at 0° C. under nitrogen was added NaH (60%, 2.0 g, 50 mmol, 4.0eq) slowly. After gas releasing was completed, dimethy carbonate (11.3g, 125 mmol, 10.0 eq) was added via syringe. The reaction mixture waswarmed to room temperature and further heated at 50° C. for 2 hours. Thereaction was then cooled down to room temperature and quenched withsaturated ammonia chloride solution. The solvent was removed in vacuoand the residue was partitioned between ethyl ether and water. Theaqueous layer was extracted with ethyl ether twice. The combined organiclayer was washed with brine, dried over anhydrous sodium sulfate,filtered and concentrated to give a colorless oil. The crude materialwas then purified by column chromatography using 5:1 hexanes:ethylacetate to give the title compound as a colorless solid.

¹H NMR (δ, CDCl₃) 12.2 (s, 1H), 3.78 (s, 3H), 3.35 (m, 4H), 2.88 (s,2H), 2.52 (t, J=9.2 Hz, 2H), 2.18 (t, J=9.2 Hz, 2H).

EXAMPLE 2 9-Hydroxy-1,5-dithia-spiro[5.5]undec-8-ene-8-carboxylic acidmethyl ester

The title product was prepared as a colorless solid according to theprocedure described in Example 1 using1,5-dithia-spiro[5.5]undecan-9-one as the starting material.

¹H NMR (δ, CDCl₃) 12.2 (s, 1H), 3.80 (s, 3H), 2.95 (m, 4H), 2.66 (s,2H), 2.45 (t, J=8.5 Hz, 2H), 2.25 (m, 2H), 2.10 (t, J=8.5 Hz, 2H).

EXAMPLE 32-Hydroxy-11,14-dithia-spiro[4,5]-5,6,7,8-tetrahydro-benzo[c]chromen-9-one

To 8-hydroxy-1,4-dithia-spiro[4.5]dec-7-ene-7-carboxylic acid methylester (1.88 g, 7.64 mmol, 1.0 eq) prepared from Example 1 and resorcinol(841 mg, 7.64 mmol, 1.0 eq) in CH₂Cl₂ (10 mL) under nitrogen at 0° C.was added methyl sulfonic acid (˜5 mL). The reaction mixture was stirredat 0° C. for 30 min and then warmed to room temperature. Water andCH₂Cl₂ were added and the mixture was partitioned between water andCH₂Cl₂. The aqueous layer was extracted twice with CH₂Cl₂. The combinedorganic layer was then washed with saturated sodium bicarbonate solutionand brine, dried over anhydrous sodium sulfate, filtered andconcentrated to give a brown oil. The crude material was then purifiedby column chromatography using 4:1 CH₂Cl₂:MeOH to give the titlecompound as a yellow semi solid.

¹H NMR (δ, CDCl₃) 7.55 (d, J=6.8 Hz, 1H), 6.80 (d, J=6.8 Hz, 1H), 6.68(s, 1H), 3.38 (m, 2H), 3.32 (m, 2H), 3.11 (s, 2H), 3.05 (t, J=10.5 Hz,2H), 2.28 (t, J=10.5 Hz, 2H). MS 307 MH⁺, 329 MNa⁺.

EXAMPLE 42-Hydroxy-11,15-dithia-spiro-[5,5]-5,6,7,8-tetrahydro-benzo[c]chromen-9-one

The title product was prepared as a brown solid according to theprocedure described in Example 3 using9-Hydroxy-1,5-dithia-spiro[5.5]undec-8-ene-8-carboxylic acid methylester as the starting material.

¹H NMR (δ, CDCl₃) 7.58 (d, J=7.5 Hz, 1H), 6.92 (d, J=7.5 Hz, 1H), 6.72(s, 1H), 3.40 (m, 2H), 3.35 (m, 2H), 3.15 (s, 2H), 3.10 (t, J=9.0 Hz,2H), 2.50 (t, J=9.0 Hz, 2H), 2.20 (m, 2H). MS 321 MH⁺, 343 MNa⁺.

EXAMPLE 52-tert-Butyl-dimethyl-silanyloxy-11,14-dithia-spiro-[4,5]-5,6,7,8-tetrahydro-benzo[c]chromen-9-one

A slurry of2-hydroxy-10,14-dithia-spiro[4,5]-5,6,7,8-tetrahydro-benzo[c]chromen-9-one(5.72 g, 18.7 mmol, 1 eq), prepared as in Example 3, in DMF (20 mL) wastreated with imidazole (1.4 g, 20.6 mmol, 1.1 eq), followed by theaddition of t-butyldimethylsilyl chloride (3.1 g, 20.6 mmol, 1.1 eq).The reaction mixture was stirred at room temperature under nitrogen for18 hours. The reaction mixture was diluted with ethyl ether and washedonce with brine. The aqueous washing was re-extracted with ethyl ethertwice. The combined organic extracts were dried (anhydrous sodiumsulphate), filtered and evaporated in vacuum to yield a yellow solidresidue. The solid residue was purified from column chromatography using5:1 hexane:ethyl acetate to yield the title compound as a light yellowsolid.

¹H NMR (δ, CDCl₃) 7.45 (d, J=7.5 Hz, 1H), 6.78 (m, 2H), 3.45 (m, 4H),3.21 (s, 2H), 3.05 (t, J=10.5 Hz, 2H), 2.36 (t, J=10.5 Hz, 2H), 1.02 (s,9H), 0.25 (s, 6H). MS 443 MH⁺.

EXAMPLE 62-Hydroxy-11,15-dithia-spiro[5,5]-5,6,7,8-tetrahydro-benzo[c]chromen-9-one

The title product was prepared as a light yellow solid according to theprocedure described in Example 5 using2-Hydroxy-11,15-dithia-spiro[5,5]5,6,7,8-tetrahydro-benzo[c]chromen-9-oneas the starting material.

¹H NMR (δ, CDCl₃) 7.48 (d, J=6.8 Hz, 1H), 6.80 (d, J=6.8 Hz, 1H), 6.78(s, 1H), 3.40 (m, 2H), 3.20 (s, 2H), 3.03 (t, J=9.0 Hz, 2H), 2.30 (t,J=9.0 Hz, 2H), 2.20 (m, 2H), 1.10 (s, 9H), 0.20 (s, 6H). MS 457 MH⁺.

EXAMPLE 72-(tert-Butyl-dimethyl-silanyloxy)-11,14-dithia-spiro[4,5]-5,6,7,8-tetrahydro-benzo[c]chromen-9-ol

A solution of2-tert-butyl-dimethyl-silanyloxy-10,14-dithia-spiro[4,5]-5,6,7,8-tetrahydro-benzo[c]chromen-9-one(5.00 g, 11.9 mmol, 1 eq) in toluene (20 mL) was cooled to −78° C. in a200 mL 3-neck round bottom flask under nitrogen. To the reaction mixturewas slowly added a toluene solution of diisobutylaluminum hydride (8.7mL of 1.5 M, 13.1 mmol, 1.1 eq), with the temperature of the reactionmixture maintained at less than −70° C. The reaction was stirred for 1hour, quenched with addition of methanol (2 mL). The resulting solutionwas diluted with dichloromethane, the solution washed with a saturatedsolution of Rochelle salt, then washed with brine, dried on anhydroussodium sulphate, filtered and evaporated to yield the crude compound asa yellow solid. The solid was purified by column chromatography using ahexane:ethyl acetate mixture (2:1) to yield the title product as a whitesolid.

¹H NMR (δ, CDCl₃) 6.92 (d, J=8.0 Hz, 1H), 6.30 (m, 2H), 5.38 (d, J=6.5Hz, 1H), 3.21 (m, 4H), 2.85˜2.55 (m, 4H), 2.41 (m, 1H), 2.11 (m, 2H),0.88 (s, 9H), 0.10 (s, 6H), MS 405, [M-H₂O]H⁺.

EXAMPLE 82-(tert-Butyl-dimethyl-silanyloxy)-11,15-dithia-spiro[5,5]-5,6,7,8-tetrahydro-benzo[c]chromen-9-ol

The title product was prepared as a white solid according to theprocedure described in Example 7 using2-Hydroxy-11,15-dithia-spiro[5,5]-5,6,7,8-tetrahydro-benzo[c]chromen-9-oneas the starting material.

¹H NMR (δ, CDCl₃) 6.95 (d, J=6.8 Hz, 1H), 6.32 (s, 1H), 6.28 (m, 1H),5.36 (d, J=6.5 Hz, 1H), 3.90˜2.81 (m, 10H), 1.12 (m, 2H), 0.85 (s, 9H),0.02 (s, 6H), MS 419, [M-H₂O]H⁺.

EXAMPLE 92-(tert-Butyl-dimethyl-silanyloxy)-{9-[4′-(2′-chloro-ethoxy)-phenyl]-11,14-spiro[4,5]-5,6,7,8-tetrahydro-9H-benzo[c]chromene

In a single neck, 100 mL round bottom flask was dissolved and stirred1-(2-chloro-ethoxy)-4-iodo-benzene (3.55 g, 10.7 mmol, 2.0 eq), intetrahydrofuran (20 mL) under nitrogen, and the mixture cooled to −78°C. After 5 minutes of stirring, a hexane solution of n-BuLi (4.28 mL of2.5 M, 10.7 mmol, 2.0 eq) was added via syringe. The reaction mixturewas then stirred for 30 min at about −78° C. A tetrahydrofuran solutionof2-(tert-butyl-dimethyl-silanyloxy)-10,14-dithia-spiro[4,5]-5,6,7,8-tetrahydro-benzo[c]chromen-9-ol(2.26 g, 5.36 mmol, 1 eq, in 10 mL), prepared as in Example 7, was thenadded, the cooling bath was removed and the reaction mixture was allowedto warm to room temperature overnight. After about 18 hours, thereaction was worked-up with addition of saturated ammonium acetatesolution and extraction with ethyl ether. The combined organic extractswere washed with brine and water, dried with anhydrous sodium sulphate,filtered and evaporated to yield a sticky semisolid residue. To thissolid was added 0.5 mL HCl in 20 mL toluene at room temperature. Themixture was stirred for 2 hours at room temperature. The reaction wasworked-up with extraction with ethyl acetate three times. The combinedorganic extracts were washed with brine and water, dried with anhydroussodium sulphate, filtered and evaporated to yield a brown oil. The titleproduct was isolated as a white semisolid foam via chromatography onsilica gel eluted with 2:1 hexanes:ethyl acetate as eluent.

¹H NMR (δ, CDCl₃) 7.18 (d, J=7.2 Hz, 2H), 6.88 (d, J=7.0 Hz, 1H), 6.72(d, J=7.2 Hz, 2H), 6.22 (d, J=7.0 Hz, 1H), 6.08 (s, 1H), 5.31 (s, 1H),4.05 (t, J=11.5 Hz, 2H), 3.62 (t, J=11.5 Hz, 2H), 3.12 (m, 4H),2.71˜2.45 (m, 2H), 2.46˜2.20 (abq, J=15.4 Hz, 2H), 2.10 (t, J=10.5 Hz,2H), 0.72 (s, 9H), 0.12 (s, 6H). MS 561 MH⁺.

EXAMPLE 102-(tert-Butyl-dimethyl-silanyloxy)-{9-[4′-(2′-chloro-ethoxy)-phenyl]-11,15-spiro[5,5]-5,6,7,8-tetrahydro-9H-benzo[c]chromene

The title product was prepared as a white semisolid according to theprocedure described in Example 9 using2-(tert-Butyl-dimethyl-silanyloxy)-11,15-dithia-spiro[5,5]-5,6,7,8-tetrahydro-benzo[c]chromen-9-olas the starting material.

¹H NMR (δ, CDCl₃) 7.15 (d, J=72. Hz, 2H), 6.88 (d, J=6.8 Hz, 1H), 6.72(d, J=7.2 Hz, 2H), 6.21 (d, J=6.8 Hz, 1H), 6.08 (d, J=1.5 Hz, 1H), 5.32(s, 1H), 4.05 (t, J=11.2 Hz, 2H), 3.62 (t, J=11.2 Hz, 2H), 2.88˜2.48 (m,3H), 2.45˜2.05 (m, 3H), 1.92˜1.34 (m, 2H), 1.15 (m, 4H), 0.80 (s, 9H),0.05 (s, 6H).

EXAMPLE 112-(Hydroxy)-{9-[4′-(2′-piperidinyl-ethoxy)-phenyl]-11,14-spiro[4,5]-5,6,7,8-tetrahydro-9H-benzo[c]chromene

To2-(tert-butyl-dimethyl-silanyloxy)-{9-[4′-(2′-chloro-ethoxy)-phenyl]-10,14-spiro[4,5]-5,6,7,8-tetrahydro-9H-benzo[c]chromene(250 mg, 0.445 mmol, 1.0 eq) in DMF (5 mL) was added catalytic amount ofKI (8 mg, 0.04 mmol, 0.1 eq) and piperidine (80 mg, 0.89 mmol, 2.0 eq).The reaction mixture was heated at 50° C. for 2 hours. CH₂Cl₂ and waterwere added, the organic layer was separated and the aqueous layerre-extracted with dichloromethane. The combined organic extracts werewashed with brine, dried (anhydrous sodium sulphate), filtered andevaporated in vacuo. The residue was purified by chromatography onsilica gel using 2% methanol/dichloromethane as an eluent to yield thetitle product as a crystalline solid.

¹H NMR (δ, CDCl₃) 7.25 (d, J=9.0 Hz, 2H), 7.05 (d, J=7.8 Hz, 1H), 6.85(d, J=9.0 Hz, 2H), 6.32 (d, J=7.8 Hz, 1H), 6.10 (s, 1H), 5.40 (s, 1H),4.15 (t, J=12.5 Hz, 2H), 3.36 (m, 4H), 3.20 (m, 2H), 2.75 (t, J=12.5 Hz,2H), 2.58 (m, 4H), 2.55 (m, 2H), 2.25 (t, J=9.8 Hz, 2H), 1.65 (m, 4H),1.50 (m, 2H).

EXAMPLE 122-(Hydroxy)-{9-[4′-(2′-piperidinyl-ethoxy)-phenyl]-11,15-spiro[5,5]-5,6,7,8-tetrahydro-9H-benzo[c]chromene

The title product was prepared as a white solid according to theprocedure described in Example 11 using2-(tert-Butyl-dimethyl-silanyloxy)-{9-[4′-(2′-chloro-ethoxy)-phenyl]-11,15-spiro[5,5]-5,6,7,8-tetrahydro-9H-benzo[c]chromeneas the starting material.

¹H NMR (δ, CDCl₃) 7.28 (d, J=8.5 Hz, 2H), 6.98 (d, J=8.0 Hz, 1H), 6.70(d, J=8.5 Hz, 2H), 6.30 (d, J=8.0 Hz, 1H), 6.12 (s, 1H), 5.48 (s, 1H),4.05 (t, J=17.8 Hz, 2H), 3.05˜2.75 (m, 6H), 2.65 (m, 4H), 2.55˜2.23 (m,4H), 2.12˜1.88 (m, 4H), 1.72 (m, 4H), 1.48 (m, 2H).

EXAMPLE 139R*-2-(Hydroxy)-{9-[4′-(2′-piperidinyl-ethoxy)-phenyl]-11,14-spiro[4,5]-5,6,7,8-tetrahydro-9H-benzo[c]chromeneand9S*-2-(Hydroxy)-{9-[4′-(2′-piperidinyl-ethoxy)-phenyl]-11,14-spiro[4,5]-5,6,7,8-tetrahydro-9H-benzo[c]chromene

The racemic mixture of (˜300 mg) was loaded onto a ChiralPak AD chiralHPLC column (21 mm I.D.×250 mm L) and eluted with 50% methanol inisopropyl alcohol at the 4 mL/min flow rate. Two peaks were collectedseparately and were removed under vacuum to yield: R* as peak one.

MS (Cl) m/z 496 (MH⁺), [α]_(CDCl3) ²⁰=+16.8.

and S* as peak two.

MS (Cl) m/z 496 (MH⁺), [α]_(CDCl3) ²⁰=−11.5.

EXAMPLE 142-(Hydroxy)-{9-[4′-(2′-pyrrolidinyl-ethoxy)-phenyl]-11,14-spiro[4,5]-5,6,7,8-tetrahydro-9H-benzo[c]chromene

The title product was prepared as a white solid according to theprocedure described in Example 11 using pyrrolidine as the base.

¹H NMR (δ, CDCl₃) 7.22 (d, J=8.0 Hz, 2H), 7.10 (d, J=6.8 Hz, 1H), 6.85(d, J=8.0 Hz, 2H), 6.40 (d, J=6.8 Hz, 1H), 6.20 (s, 1H), 5.90 (s, 1H),4.15 (t, J=10.5 Hz, 2H), 3.40˜3.22 (m, 4H), 2.95 (t, J=10.5 Hz, 2H),2.80˜2.65 (m, 4H), 2.58 (m, 4H), 2.55 (m, 2H), 1.85 (m, 4H). MS (CI) m/z482 (MH⁺).

EXAMPLE 152-(Hydroxy)-{9-[4′-(2′-diethyl-ethoxy)-phenyl]-11,14-spiro[4,5]-5,6,7,8-tetrahydro-9H-benzo[c]chromene

The title product was prepared as a white semisolid according to theprocedure described in Example 11 using diethyl amine as the base.

¹H NMR (δ, CDCl₃) 7.25 (d, J=6.5 Hz, 2H), 7.15 (d, J=6.8 Hz, 1H), 6.88(d, J=6.5 Hz, 2H), 6.48 (d, J=6.8 Hz, 1H), 6.25 (s, 1H), 5.88 (s, 1H),4.12 (t, J=11.5 Hz, 2H), 3.42˜3.20 (m, 4H), 2.85 (t, J=11.5 Hz, 2H),2.82˜2.68 (m, 4H), 2.65 (m, J=12.5 Hz, 4H), 2.55 (m, 2H), 1.15 (t,J=12.5 Hz, 6H).

MS (Cl) m/z 484 (MH⁺).

EXAMPLE 16 2″,2″-Dimethyl-propionicacid-{9-[4′-(2′-piperidinyl-ethoxy)-phenyl]-11,14-spiro[4,5]-5,6,7,8-tetrahydro-9H-benzo[c]chromen-2-ylester

To an ice-cooled and stirred slurry of2-(hydroxy)-{9-[4′-(2′-piperidinyl-ethoxy)-phenyl]-10,14-spiro[4,5]-5,6,7,8-tetrahydro-9H-benzo[c]chromene(0.200 g, 0.404 mmol), prepared as in Example 11, in dichloromethane (5mL) under nitrogen, was added triethylamine (0.11 mL, 0.808 mmol, 2.0eq) at 0° C. After about 10 minutes the reaction mixture was observed tobecome clear. To the reaction mixture was then slowly added (over aperiod of about 5 minutes) 2,2-dimethylpropionyl chloride (i.e.,pivaloyl chloride, 0.075 mL, 0.606 mmol, 1.5 eq.). The cooling bath wasthen removed and the reaction mixture was allowed to warm to roomtemperature overnight. To the reaction mixture was then added saturatedNaHCO₃ solution and the resulting solution was stirred at roomtemperature for 1 hour. The organic layer was separated and the aqueouslayer re-extracted with dichloromethane. The combined organic extractswere washed with brine, dried (anhydrous sodium sulphate), filtered andevaporated in vacuo. The residue was purified by chromatography onsilica gel using 2% methanol/dichloromethane as an eluent to yield thetitle product as an ivory, crystalline solid.

¹H NMR (δ, CDCl₃) 7.26 (d, J=8.5 Hz, 2H), 7.15 (d, J=8.0 Hz, 1H), 6.82(d, J=8.5 Hz, 2H), 6.60 (d, J=8.0 Hz, 1H), 6.42 (s, 1H), 5.51 (s, 1H),4.08 (t, J=7.8 Hz, 2H), 3.28 (m, 4H), 2.75 (t, J=7.8 Hz, 2H), 2.70˜2.38(m, 4H), 2.25 (t, J=7.8 Hz, 2H), 1.62 (m, 4H), 1.48 (m, 2H), 1.32 (s,9H). MS 580 MH⁺, 602 MNa⁺.

EXAMPLE 17 2″,2″-Dimethyl-propionicacid-{9-[4′-(2′-piperidinyl-ethoxy)-phenyl]-11,15-spiro[5,5]-5,6,7,8-tetrahydro-9H-benzo[c]chromen-2-ylester

The title product was prepared as a white semisolid according to theprocedure described in Example 14 using2-(Hydroxy)-{9-[4′-(2′-piperidinyl-ethoxy)-phenyl]-11,15-spiro[5,5]-5,6,7,8-tetrahydro-9H-benzo[c]chromeneas the starting material.

¹H NMR (δ, CDCl₃) 7.28 (d, J=8.4 Hz, 2H), 7.14 (d, J=7.8 Hz, 1H), 6.82(d, J=8.4 Hz, 2H), 6.60 (d, J=7.8 Hz, 1H), 6.42 (s, 1H), 5.50 (s, 1H),4.12 (t, J=6.5 Hz, 2H), 3.05˜2.76 (m, 4H), 2.80 (t, J=6.5 Hz, 2H),2.70˜2.40 (m, 8H), 2.15˜1.88 (m, 4H) 1.68 (m, 4H), 1.48 (m, 2H), 1.30(s, 9H). MS 594 MH⁺, 616 MNa⁺.

EXAMPLE 182-(hydroxy)-{9-[4′-(2′-piperidinyl-ethoxy)-phenyl]-11,15-spiro[5,5]-5,6,7,8-tetrahydro-9H-benzo[c]chrome-11,11,15,15-tetraoxide

To2-(hydroxy)-{9-[4′-(2′-piperidinyl-ethoxy)-phenyl]-11,15-spiro[5,5]-5,6,7,8-tetrahydro-9H-benzo[c]chromene(300 mg, 0.521 mmol, 1.0 eq), prepared from Example 10 in the mixturesolution of ethylene glycol (0.5 mL), CH₂Cl₂ (0.5 mL) and acetonitrile(4 mL) at room temperature was added OXONE (640 mg, 1.04 mmol, 2.0 eq)in one portion. The reaction mixture was stirred for 4 hours at roomtemperature. The solvent was removed and the residue was partitionedbetween CH₂Cl₂ and water. The organic layer was separated and theaqueous layer re-extracted with dichloromethane. The combined organicextracts were washed with brine, dried (anhydrous sodium sulphate),filtered and evaporated in vacuo. The residue, KI (8 mg, 0.05 mmol, 0.1eq) and piperidine (90 mg, 1.04 mmol, 2.0 eq) in DMF (5 mL) were heatedat 50° C. for 2 hours. The reaction mixture was then partitioned betweenCH₂Cl₂ and water. The organic layer was washed with brine, dried overanhydrous sodium sulfate then purified by chromatography on silica gelusing 2% methanol/dichloromethane as an eluent to yield the titleproduct as an ivory, crystalline solid.

¹H NMR (δ, CDCl₃) 7.28 (d, J=8.0 Hz, 2H), 7.10 (d, J=7.5 Hz, 1H), 6.90(d, J=8.0 Hz, 2H), 6.42 (d, J=7.5 Hz, 1H), 6.12 (s, 1H), 5.45 (s, 1H),4.10 (t, J=11.5 Hz, 2H), 3.75 (m, 4H), 3.25 (m, 2H), 2.80 (t, J=11.5 Hz,2H), 2.62 (m, 4H), 2.58 (m, 2H), 2.18 (t, J=8.5 Hz, 2H), 1.55 (m, 4H),1.48 (m, 2H).

MS, 574, MH⁺.

EXAMPLE 19 9R*-2″,2″-Dimethyl-propionicacid-{9-[4′-(2′-piperidinyl-ethoxy)-phenyl]-11,14-spiro[4,5]-5,6,7,8-tetrahydro-9H-benzo[c]chromen-2-ylester and 9S*-2″,2″-Dimethyl-propionicacid-{9-[4′-(2′-piperidinyl-ethoxy)-phenyl]-11,14-spiro[4,5]-5,6,7,8-tetrahydro-9H-benzo[c]chromen-2-ylester

The racemic mixture of (˜200 mg) was loaded onto a ChiralPak AD chiralHPLC column (21 mm I.D.×250 mm L) and eluted with isopropyl alcohol atthe 4 mL/min flow rate. Two peaks were collected separately and wereremoved under vacuum to yield: R* as peak one.

MS (Cl) m/z 580 (MH⁺).

and S* as peak two.

MS (Cl) m/z 580 (MH⁺).

EXAMPLE 20 9R*-2″,2″-Dimethyl-propionicacid-{9-[4′-(2′-piperidinyl-ethoxy)-phenyl]-11,15-spiro[5,5]-5,6,7,8-tetrahydro-9H-benzo[c]chromen-2-ylester and 9S*-2″,2″-Dimethyl-propionicacid-{9-[4′-(2′-piperidinyl-ethoxy)-phenyl]-11,15-spiro[5,5]-5,6,7,8-tetrahydro-9H-benzo[c]chromen-2-ylester

The racemic mixture of (˜200 mg) was loaded onto a ChiralPak AD chiralHPLC column (21 mm I.D.×250 mm L) and eluted with isopropyl alcohol atthe 4 mL/min flow rate. Two peaks were collected separately and wereremoved under vacuum to yield: R* as peak one.

MS (Cl) m/z 594 (MH⁺).

and S* as peak two.

MS (Cl) m/z 594 (MH⁺).

EXAMPLE 219-[4′-(2′-Piperidin-1′-yl-ethoxy)-phenyl]-9H-benzo[c]chromene-2,7-diol

To2-(Hydroxy)-{9-[4′-(2′-piperidinyl-ethoxy)-phenyl]-10,14-spiro[4,5]-5,6,7,8-tetrahydro-9H-benzo[c]chromene(225 mg, 0.48 mmol, 1 eq) in THF (5 mL) and water (1 mL) was addedHg(ClO₄)₂ (4M aqueous solution, 130 mL, 0.52 mmol, 1.08 eq) followed byCaCO₃ (52 mg, 0.52 mmol, 1.08 eq) at room temperature. The reaction wasworked up after 5 min. The solvent was removed and the residue waspartitioned between CH₂Cl₂ and water. The organic layer was separatedand the aqueous layer re-extracted with dichloromethane. The combinedorganic extracts were washed with brine, dried (anhydrous sodiumsulphate), filtered and evaporated in vacuo. The residue was purified bychromatography on silica gel using 2% methanol/dichloromethane as aneluent to yield the title product as a white solid.

¹H NMR (δ, CDCl₃) 7.52 (d, J=6.8 Hz, 2H), 6.88 (d, J=7.0 Hz, 1H), 6.71(d, J=6.8 Hz, 2H), 6.58 (d, J=7.0 Hz, 1H), 6.52 (s, 1H), 6.62 (s, 1H),5.88 (s, 1H), 4.05 (t, J=12.5 Hz, 2H), 2.81 (t, J=12.5 Hz, 2H), 2.53 (m,4H), 1.65 (m, 4H), 1.55 (m, 2H). MS, 443 MNa⁺.

EXAMPLE 222-(tert-Butyl-dimethyl-silanyloxy)-9-[4-(2-chloro-ethoxy)-phenyl]-5,6-dihydro-8H,9H-benzo[c]chromen-7-one

To2-(tert-butyl-dimethyl-silanyloxy)-{9-[4′-(2′-chloro-ethoxy)-phenyl]-10,14-spiro[4,5]-5,6,7,8-tetrahydro-9H-benzo[c]chromene(310 mg, 0.553 mmol, 1 eq) in THF (5 mL) and water (1 mL) was addedHg(ClO₄)₂ (243 mg, 0.608 mmol, 1.08 eq) followed by CaCO₃ (61 mg, 0.608mmol, 1.08 eq) at room temperature. The reaction was worked up after 5min. The solvent was removed and the residue was partitioned betweenCH₂Cl₂ and water. The organic layer was separated and the aqueous layerre-extracted with dichloromethane. The combined organic extracts werewashed with brine, dried (anhydrous sodium sulphate), filtered andevaporated in vacuo. The residue was purified by chromatography onsilica gel using 2% methanol/dichloromethane as an eluent to yield thetitle product as a white foam.

¹H NMR (δ, CDCl₃) 7.12 (d, J=12.5 Hz, 2H), 6.91 (d, J=9.5 Hz, 1H), 6.72(d, J=12.5 Hz, 2H), 6.24 (d, J=9.5 Hz, 1H), 6.12 (s, 1H), 5.36 (s, 1H),4.05 (t, J=12.5 Hz, 2H), 3.65 (t, J=12.5 Hz, 2H), 2.85˜2.45 (m, 6H),0.82 (s, 9H), 0.02 (s, 6H).

EXAMPLE 23

To2-(tert-Butyl-dimethyl-silanyloxy)-9-[4-(2-chloro-ethoxy)-phenyl]-5,6-dihydro-8H,9H-benzo[c]chromen-7-one(250 mg, 0.52 mmol, 1.0 eq) in THF (5 mL) at −78° C. was added dropwiseof TMSOTf (12. mg, 0.05 mmol, 0.1 eq) followed by1,2-bis(trimethylsiloxy)ethane (118 mg, 0.57 mmol, 1.1 eq). The reactionmixture was stirred at −78° C. for 6 hours and then queched by MeOH (1mL). The solvent was removed and the residue was partitioned betweenCH₂Cl₂ and water. The organic layer was separated and the aqueous layerre-extracted with dichloromethane. The combined organic extracts werewashed with brine, dried (anhydrous sodium sulphate), filtered andevaporated in vacuo. The residue (˜200 mg, 0.38 mmol, 1.0 eq), KI (7 mg,0.04 mmol, 0.1 eq) and piperidine (65 mg, 0.76 mmol, 2.0 eq) in DMF (5mL) were heated at 50° C. for 2 hours. The reaction mixture was thenpartitioned between CH₂Cl₂ and water. The organic layer was washed withbrine, dried over anhydrous sodium sulfate then purified bychromatography on silica gel using 2% methanol/dichloromethane as aneluent to yield the title product as an ivory, crystalline solid.

¹H NMR (δ, CDCl₃) 7.30 (d, J=7.8 Hz, 2H), 7.10 (d, J=7.5 Hz, 1H), 6.95(d, J=7.8 Hz, 2H), 6.42 (d, J=7.5 Hz, 1H), 625 (s, 1H), 5.55 (s, 1H),4.23 (t, J=12.5 Hz, 2H), 4.05 (m, 4H), 3.25 (m, 2H), 2.84 (t, J=12.5 Hz,2H), 2.64 (m, 4H), 2.60 (m, 2H), 2.35 (t, J=9.8 Hz, 2H), 1.75 (m, 4H),1.55 (m, 2H). MS, 464, MH⁺.

TABLE 1

ID No X Y R¹/R² I R³ Calc. MW  3 S S ═O 1 2-OH 306.40  4 S S ═O 2 2-OH320.43  5 S S ═O 1 2-OTBS 420.66  6 S S ═O 2 2-OTBS 434.69  7 S S —OH 12-OTBS 422.68  8 S S —OH 2 2-OTBS 436.71  9 S S

1 2-OTBS 561.27 10 S S

2 2-OTBS 575.30 11 S S

1 2-OH 495.70 12 S S

2 2-OH 509.73 13 S S

1 2-OH 481.67 14 S S

1 2-OH 483.69 15 S S

1 2-OPIV 579.81 16 S S

2 2-OPIV 593.84 17 SO₂ SO₂

2 2-OH 573.73 18 O O

1 2-OH 463.57 R*-(+)-11 S S

1 2-OH 495.70 S*-(−)-11 S S

1 2-OH 495.70 R*-15 S S

1 2-OPIV 579.81 S*-15 S S

1 2-OPIV 579.81 R*-16 S S

2 2-OPIV 593.84 S*-16 S S

2 2-OPIV 593.84

EXAMPLE 24 MCF-7 Cell Proliferation Assay

This assay was run according to the procedure described by Welshons, etal., (Breast Cancer Res. Treat., 1987, 10(2), 169-75), with minormodification.

Briefly, MCF-7 cells (from Dr. C. Jordan, Northwestern University) weremaintained in RPMI 1640 phenol red free medium (Gibco) in 10% FBS(Hyclone), supplemented with bovine insulin and non-essential amino acid(Sigma). The cells were initially treated with 4-hydroxyltamoxifen (10⁻⁸M) and let stand at 37° C. for 24 hours. Following this incubation withtamoxifen, the cells were treated with compounds at variousconcentrations.

Compounds to be tested in the agonist mode were added to the culturemedia at varying concentrations. Compounds to be treated in theantagonist mode were prepared similarly, and 10 nM 17β-estradiol wasalso added to the culture media. The cells were incubated for 24 hoursat 37° C. Following this incubation, 0.1 □Ci of ¹⁴C-thymidine (56mCi/mmol, Amersham) was added to the culture media and the cells wereincubated for an additional 24 hours at 37° C. The cells were thenwashed twice with Hank's buffered salt solution (HBSS) (Gibco) andcounted with a scintillation counter. The increase in the ¹⁴C-thymidinein the compound treated cells relative to the vehicle control cells werereported as percent increase in cell proliferation.

Representative compound of the present invention were tested accordingto the procedure described above, with results as listed in Table. 2.

TABLE 2 ID No Agonist (No.) (nM) Antagonist (No.) (nM) 11 NA 1060 12 NA686 13 NA >10000 14 NA 4970 R*-11 NA 672 S*-11 NA >10000 R*-15 NA 769.5S*-15 NA >10000 R*-16 NA 270.7 S*-16 NA >10000 17 NA >10000 NA indicatesno detected activity at test concentration.

EXAMPLE 25 Alkaline Phosphatase Assay in Human Endometrial IshikawaCells

This assay was run according to the procedure described by Albert etal., Cancer Res, (9910), 50(11), 330-6-10, with minor modification.

Ishikawa cells (from ATCC) were maintained in DMEM/F12 (1:1) phenol redfree medium (Gibco) supplemented with 10% calf serum (Hyclone). 24 hoursprior to testing, the medium was changed to DMEM/F12 (1:1) phenol redfree containing 2% calf serum.

Compounds to be tested in the agonist mode were added to the culturemedia at varying concentrations. Compounds to be treated in theantagonist mode were prepared similarly, and 10 nM 17β-estradiol wasalso added to the culture media. The cells were then incubated at 37° C.for 3 days. On the fourth day, the media was remove, 1 volume of 1×Dilution Buffer (Clontech) was added to the well followed by addition of1 volume of Assay Buffer (Clontech). The cells were then incubated atroom temperature for 5 minutes. 1 volume of freshly preparedChemiluminescence Buffer (1 volume of chemiluminescent substrate (CSPD)in 19 volume Chemiluminescent Enhancer with final concentration of CSPDat 1.25 mM; Sigma Chemical Co.) was added. The cells were incubated atroom temperature for 10 minutes and then quantified on a luminometer.The increase of chemiluminescence over vehicle control was used tocalculate the increase in alkaline phosphatase activity.

Representative compound of the present invention were tested accordingto the procedure described above, with results as listed in Table 3.

TABLE 3 ID No Agonist (No.) (nM) Antagonist (No.) (nM) 11 NA 29.6 12 NA35.1 13 NA 1048 14 NA 65.9 R*-11 NA 41.9 S*-11 NA 1018 R*-15 NA 219.5S*-15 NA >10000 R*-16 NA 25.8 S*-16 NA >10000 17 NA >10000 NA indicatesno detected activity at test concentration;

EXAMPLE 26

As a specific embodiment of an oral composition, 100 mg of the compound11, prepared as in Example 11 is formulated with sufficient finelydivided lactose to provide a total amount of 580 to 590 mg to fill asize O hard gel capsule.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

1-7. (canceled)
 8. A method of treating a disorder mediated by anestrogen receptor, in a subject in need thereof comprising administeringto the subject a therapeutically effective amount of a compound offormula (I)

wherein

represents a single or double bond, X Y are selected from the groupconsisting of O, S, SO and SO₂; Z is selected from the group consistingof O and S; R¹ is selected from the group consisting of hydrogen, alkyl,cycloalkyl, aryl, aralkyl, heteroaryl and heteroaryl-alkyl; wherein thecycloalkyl, aryl, aralkyl, heteroaryl or heteroaryl-alkyl group isoptionally substituted with one or more substituents independentlyselected from halogen, hydroxy, alkyl, alkoxy, —SH, —S(alkyl), SO₂, NO₂,CN, CO₂H, R^(C), —OR^(C), —SO₂—NR^(D)R^(E), —NR^(D)R^(E),NR^(D)—SO₂—R^(F), -(alkyl)₀₋₄-C(O)NR^(D)R^(E),(alkyl)₀₋₄-NR^(D)—C(O)—R^(F), -(alkyl)₀₋₄-(Q)₀₋₁-(alkyl)₀₋₄-NR^(D)R^(E),-(alkyl)₀₋₄-(Q)₀₋₁-(alkyl)₀₋₄-C(O)—OR^(F),-(alkyl)₀₋₄-(Q)₀₋₁-(alkyl)₀₋₄-C(O)—NR^(D)R^(E) or-(alkyl)₀₋₄-C(O)-(alkyl)₀₋₄-C(O)—OR^(F); wherein R^(C) is selected fromthe group consisting of alkyl, cycloalkyl, cycloalkyl-alkyl, aryl,aralkyl, heteroaryl, heteroaryl-alkyl, heterocycloalkyl andheterocycloalkyl-alkyl; wherein the cycloalkyl, cycloalkyl-alkyl, aryl,aralkyl, heteroaryl, heteroaryl-alkyl, heterocycloalkyl orheterocycloalkyl-alkyl group is optionally substituted with one or moresubstituents independently selected from halogen, hydroxy, alkyl,alkoxy, —SH, —S(alkyl), SO₂, NO₂, CN, CO₂H, R^(C), —SO₂—NR^(D)R^(E),NR^(D)R^(E), NR^(D)—SO₂—R^(F), -(alkyl)₀₋₄-C(O)—NR^(D)R^(E),-(alkyl)₀₋₄-NR^(D)—C(O)—R^(F),-(alkyl)₀₋₄-(Q)₀₋₁-(alkyl)₀₋₄-NR^(D)R^(E),-(alkyl)₀₋₄-(Q)₀₋₁-(alkyl)₀₋₄-C(O)—OR^(F),-(alkyl)₀₋₄-(Q)₀₋₁-(alkyl)₀₋₄-C(O)—NR^(D)R^(E) or-(alkyl)₀₋₄-C(O)-(alkyl)₀₋₄-C(O)—OR^(F); wherein Q is selected from thegroup consisting of O, S, NH, N(alkyl) and —CH═CH—; wherein R^(D) andR^(E) are each independently selected from the group consisting ofhydrogen and alkyl; alternatively R^(D) and R^(E) are taken togetherwith the nitrogen atom to which they are bound to form a 4 to 8 memberedring selected from the group consisting of heteroaryl orheterocycloalkyl; wherein the heteroaryl or heterocycloalkyl group isoptionally substituted with one or more substituents independentlyselected from halogen, hydroxy, alkyl, alkoxy, carboxy, amino,alkylamino, dialkylamino, nitro or cyano; wherein R^(F) is selected fromthe group consisting of hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl,aryl, aralkyl, heteroaryl, heteroaryl-alkyl, heterocycloalkyl andheterocycloalkyl-alkyl; wherein the cycloalkyl, aryl, heteroaryl,heteroaryl-alkyl, heterocycloalkyl or heterocycloalkyl-alkyl group isoptionally substituted with one or more substituents independentlyselected from halogen, hydroxy, alkyl, alkoxy, carboxy, amino,alkylamino, dialkylamino, nitro or cyano; R² is selected from the groupconsisting of hydroxy, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl andheteroaryl-alkyl; wherein the cycloalkyl, aryl, aralkyl, heteroaryl orheteroaryl-alkyl group is optionally substituted with one or moresubstituents independently selected from halogen, hydroxy, alkyl,alkoxy, —SH, —S(alkyl), SO₂, NO₂, CN, CO₂H, R^(C), —OR^(C),—SO₂—NR^(D)R^(E), —NR^(D)R^(E), NR^(D)—SO₂—R^(F),-(alkyl)₀₋₄-C(O)NR^(D)R^(E), (alkyl)₀₋₄-NR^(D)—C(O)—R^(F),-(alkyl)₀₋₄-(Q)₀₋₁-(alkyl)₀₋₄-NR^(D)R^(E),-(alkyl)₀₋₄-(Q)₀₋₁-(alkyl)₀₋₄-C(O)—OR^(F),-(alkyl)₀₋₄-(Q)₀₋₁-(alkyl)₀₋₄-C(O)—NR^(D)R^(E) or-(alkyl)₀₋₄-C(O)-(alkyl)₀₋₄-C(O)—OR^(F); alternatively R¹ and R² aretaken together with the carbon atom to which they are bound to formC(O); m is an integer selected from 0 to 4; R³ is independently selectedfrom the group consisting of halogen, hydroxy, R^(C), amino, alkylamino,dialkylamino, nitro, cyano, SO₂, —C(O)R^(G), —C(O)OR^(G), —OC(O)R^(G),—OC(O)OR^(G), —OC(O)N(R^(G))₂, —N(R^(G))C(O)R^(G), —OSi(R^(G))₃—OR^(G),—SO₂N(R^(G))₂, —O-(alkyl)₁₋₄-C(O)R^(G) and —O-(alkyl)₁₋₄-C(O)OR^(G);wherein each R^(G) is independently selected from hydrogen, alkyl, aryl,aralkyl and 1,7,7-trimethyl-2-oxabicyclo[2.2.1]heptan-3-one; wherein thealkyl, aryl or aralkyl group is optionally substituted with one or moresubstituents independently selected from alkyl, halogenated alkyl,alkoxy, halogen, hydroxy, nitro, cyano, —OC(O)-alkyl or —C(O)O-alkyl;alternatively two R^(G) groups are taken together with the nitrogen atomto which they are bound to form a heterocycloalkyl group; wherein theheterocycloalkyl group is optionally substituted with one or moresubstituents independently selected from halogen, hydroxy, alkyl,alkoxy, carboxy, amino, alkylamino, dialkylamino, nitro or cyano; 1 isan integer selected from 0,
 1. 9. The method of claim 8, wherein thedisorder mediated by an estrogen receptor is selected from the groupconsisting of hot flashes, vaginal dryness, osteopenia, osteoporosis,hyperlipidemia, loss of cognitive function, degenerative brain diseases,cardiovascular diseases, cerebrovascular diseases, cancer of the breasttissue, hyperplasia of the breast tissue, cancer of the endometrium,hyperplasia of the endometrium, cancer of the cervix, hyperplasia of thecervix, cancer of the prostate, hyperplasia of the prostate,endometriosis, uterine fibroids, osteoarthritis and contraception. 10.The method of claim 8, wherein the disorder mediated by an estrogenreceptor is selected from the group consisting of osteoporosis, hotflashes, vaginal dryness, breast cancer and endometriosis.
 11. A methodof treating a disorder mediated by an estrogen receptor in a subject inneed thereof comprising administering to the subject a therapeuticallyeffective amount of the composition of claim
 6. 12. A method ofcontraception comprising co-therapy with a therapeutically effectiveamount of a compound of formula (I)

wherein

represents a single or double bond, X, Y are selected from the groupconsisting of O, S, SO and SO₂; Z is selected from the group consistingof O and S; R¹ is selected from the group consisting of hydrogen, alkyl,cycloalkyl, aryl, aralkyl, heteroaryl and heteroaryl-alkyl; wherein thecycloalkyl, aryl, aralkyl, heteroaryl or heteroaryl-alkyl group isoptionally substituted with one or more substituents independentlyselected from halogen, hydroxy, alkyl, alkoxy, —SH, —S(alkyl), SO₂, NO₂,CN, CO₂H, R^(C), —OR^(C), —SO₂—NR^(D)R^(E), —NR^(D)R^(E),NR^(D)—SO₂—R^(F), -(alkyl)₀₋₄-C(O)NR^(D)R^(E),(alkyl)₀₋₄-NR^(D)—C(O)—R^(F), -(alkyl)₀₋₄-(Q)₀₋₁-(alkyl)₀₋₄-NR^(D)R^(E),-(alkyl)₀₋₄-(Q)₀₋₁-(alkyl)₀₋₄-C(O)—OR^(F),-(alkyl)₀₋₄-(Q)₀₋₁-(alkyl)₀₋₄-C(O)—NR^(D)R^(E) or-(alkyl)₀₋₄-C(O)-(alkyl)₀₋₄-C(O)—OR^(F); wherein R^(C) is selected fromthe group consisting of alkyl, cycloalkyl, cycloalkyl-alkyl, aryl,aralkyl, heteroaryl, heteroaryl-alkyl, heterocycloalkyl andheterocycloalkyl-alkyl; wherein the cycloalkyl, cycloalkyl-alkyl, aryl,aralkyl, heteroaryl, heteroaryl-alkyl, heterocycloalkyl orheterocycloalkyl-alkyl group is optionally substituted with one or moresubstituents independently selected from halogen, hydroxy, alkyl,alkoxy, —SH, —S(alkyl), SO₂, NO₂, CN, CO₂H, R^(C), —SO₂—NR^(D)R^(E),NR^(D)R^(E), NR^(D)—SO₂—R^(F), -(alkyl)₀₋₄-C(O)—NR^(D)R^(E),-(alkyl)₀₋₄-NR^(D)—C(O)—R^(F),-(alkyl)₀₋₄-(Q)₀₋₁-(alkyl)₀₋₄-NR^(D)R^(E),-(alkyl)₀₋₄-(Q)₀₋₁-(alkyl)₀₋₄-C(O)—OR^(F),-(alkyl)₀₋₄-(Q)₀₋₁-(alkyl)₀₋₄-C(O)—NR^(D)R^(E) or-(alkyl)₀₋₄-C(O)-(alkyl)₀₋₄-C(O)—OR^(F); wherein Q is selected from thegroup consisting of O, S, NH, N(alkyl) and —CH═CH—; wherein R^(D) andR^(E) are each independently selected from the group consisting ofhydrogen and alkyl; alternatively R^(D) and R^(E) are taken togetherwith the nitrogen atom to which they are bound to form a 4 to 8 memberedring selected from the group consisting of heteroaryl orheterocycloalkyl; wherein the heteroaryl or heterocycloalkyl group isoptionally substituted with one or more substituents independentlyselected from halogen, hydroxy, alkyl, alkoxy, carboxy, amino,alkylamino, dialkylamino, nitro or cyano; wherein R^(F) is selected fromthe group consisting of hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl,aryl, aralkyl, heteroaryl, heteroaryl-alkyl, heterocycloalkyl andheterocycloalkyl-alkyl; wherein the cycloalkyl, aryl, heteroaryl,heteroaryl-alkyl, heterocycloalkyl or heterocycloalkyl-alkyl group isoptionally substituted with one or more substituents independentlyselected from halogen, hydroxy, alkyl, alkoxy, carboxy, amino,alkylamino, dialkylamino, nitro or cyano; R² is selected from the groupconsisting of hydroxy, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl andheteroaryl-alkyl; wherein the cycloalkyl, aryl, aralkyl, heteroaryl orheteroaryl-alkyl group is optionally substituted with one or moresubstituents independently selected from halogen, hydroxy, alkyl,alkoxy, —SH, —S(alkyl), SO₂, NO₂, CN, CO₂H, R^(C), —OR^(C),—SO₂—NR^(D)R^(E), —NR^(D)R^(E), NR^(D)—SO₂—R^(F),-(alkyl)₀₋₄-C(O)NR^(D)R^(E), (alkyl)₀₋₄-NR^(D)—C(O)—R^(F),-(alkyl)₀₋₄-(Q)₀₋₁-(alkyl)₀₋₄NR^(D)R^(E),-(alkyl)₀₋₄-(Q)₀₋₁-(alkyl)₀₋₄-C(O)—OR^(F),-(alkyl)₀₋₄-(Q)₀₋₁-(alkyl)₀₋₄-C(O)—NR^(D)R^(E) or-(alkyl)₀₋₄-C(O)-(alkyl)₀₋₄-C(O)—OR^(F); alternatively, R¹ and R² aretaken together with the carbon atom to which they are bound to formC(O); m is an integer selected from 0 to 4; R³ is independently selectedfrom the group consisting of halogen, hydroxy, R^(C), amino, alkylamino,dialkylamino, nitro, cyano, SO₂, —C(O)R^(G), —C(O)OR^(G), —OC(O)R^(G),—OC(O)OR^(G), —OC(O)N(R^(G))₂, —N(R^(G))C(O)R^(G), —OSi(R^(G))₃—OR^(G),—SO₂N(R^(G))₂, —O-(alkyl)₁₋₄-C(O)R^(G) and —O-(alkyl)₁₋₄-C(O)OR^(G);wherein each R^(G) is independently selected from hydrogen, alkyl, aryl,aralkyl, and 1,7,7-trimethyl-2-oxabicyclo[2.2.1]heptan-3-one; whereinthe alkyl, aryl or aralkyl group is optionally substituted with one ormore substituents independently selected from alkyl, halogenated alkyl,alkoxy, halogen, hydroxy, nitro, cyano, —OC(O)-alkyl or —C(O)O-alkyl;alternatively two R^(G) groups are taken together with the nitrogen atomto which they are bound to form a heterocycloalkyl group; wherein theheterocycloalkyl group is optionally substituted with one or moresubstituents independently selected from halogen, hydroxy, alkyl,alkoxy, carboxy, amino, alkylamino, dialkylamino, nitro or cyano; 1 isan integer selected from 0,
 1. and a progestogen or a progestogenantagonist.